Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators

ABSTRACT

and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/851,322 filed on Dec. 21, 2017 which is a continuation of U.S.application Ser. No. 15/095,467 filed on Apr. 11, 2016, which is acontinuation of International Application No. PCT/EP2014/071593 havingan international filing date of Oct. 9, 2014, the entire contents ofwhich are incorporated herein by reference, and which claims the benefitof and priority to U.S. Provisional Application Ser. No. 61/890,127,filed Oct. 11, 2013, and to Chinese International Application Serial No.PCT/CN2014/086380, filed Sep. 12, 2014, both of which are herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to substituted sulfonamide compounds,their manufacture, pharmaceutical compositions containing them and theiruse as Transient Receptor Potential (TRP) channel antagonists.

BACKGROUND OF THE INVENTION

TRP channels are a class of ion channels found on the plasma membrane ofa variety of human (and other animal) cell tyl)es. There are at least 28known human TRP channels which are broken into a number of families orgroups based upon sequence homology and function. TRPA1 is anon-selective cation conducting channel that modulates membranepotential via flux of sodium, potassium and calcium. TRPA1 has beenshown to be highly expressed in the human dorsal root ganglion neuronsand peripheral sensory nerves. In humans, TRPA1 is activated by a numberof reactive compounds such as acrolein, allylisothiocyanate, ozone aswell as unreactive compounds such as nicotine and menthol and is thusthought to act as a ‘chemosensor.’

Many of the known TRPA1 agonists are irritants that cause pain,irritation and neurogenic inflammation in humans and other animals.Therefore, it would be expected that TRPA1 antagonists or agents thatblock the biological effect of TRPA1 channel activators would be usefulin the treatment of diseases such as asthma and its exacerbations,chronic cough and related maladies as well as being useful for thetreatment of acute and chronic pain. Recently, it has also been shownthat products of tissue damage and oxidative stress, e.g.4-hydroxynonenal and related compounds, activate the TRPA1 channel Thisfinding provides additional rationale for the utility of small moleculeTRPA1 antagonists in the treatment of diseases related to tissue damage,oxidative stress and bronchial smooth muscle contraction such as asthma,chronic obstructive pulmonary disease (COPD), occupational asthma, andvirally-induced lung inflammation. Moreover, recently findings havecorrelated activation of TRPA1 channels with increased pain perception(Kosugi et al., J. Neurosci 27, (2007) 4443-4451; Kremayer et al.,Neuron 66 (2010) 671-680; Wei et al., Pain 152 (2011) 582-591); Wei etal., Neurosci Lett 479 (2010) 253-256)) providing additional rationalefor the utility of small molecule TRPA1 inhibitors in the treatment ofpain disorders.

SUMMARY OF THE INVENTION

The invention provides a compound of the invention which is a compoundof Formula I:

wherein:

(1) A

is B is B¹ and R⁵ is R^(5a); or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a); or

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a);

B is B¹, B², B³ or B⁴;

B¹ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or6-membered heteroaryl of B′ is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyland (C₃-C₇)cycloalkyl;

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andwherein when B³ is pyrimidinyl which is attached to the remainder offormula I at the 4 and 6 positions of the pyrimidinyl, then R^(5a) isnot pyrrolidinyl or substituted pyrrolidinyl;

B⁴ is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any5-membered heteroaryl or 6-membered heteroaryl of B⁴ is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R² is halogen, (C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² isoptionally substituted with one or more groups independently selectedfrom halogen, —OH and —O(C₁-C₆)alkyl;

each R^(3a) is independently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3b) group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)groups are independently selected from H and (C₁-C₆)alkyl;

one R^(3b)′ group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)′groups are independently selected from H and (C₁-C₆)alkyl;

two R^(3c) groups attached to different non-adjacent carbon atoms arecombined to form a (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linkeris optionally substituted with one or more groups independently selectedfrom halogen and (C₁-C₆)alkyl, and the remaining R^(3c) groups areindependently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3d) group is halogen, (C₁-C₆)alkyl or CN and the remaining R^(3d)groups are independently selected from H, halogen and (C₁-C₆)alkyl,wherein any (C₁-C₆)alkyl of R^(3d) is optionally substituted with one ormore groups independently selected from halogen, —OH and —O(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R⁵ is R^(5a) or R^(5b);

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₇)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₇)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle ofR^(5b) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl, and wherein any 5-membered heterocycle of R^(5b)is substituted with one or more groups independently selected fromhalogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention which is acompound of formula II:

wherein:

(1) A is

B is B¹ and R⁵ is R^(5a); or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a); or

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a); or

(6) A is

B is B⁵ and R⁵ is R^(5a); or

(7) A is

B is B³ and R⁵ is R^(5a);

B is B¹, B², B³, B⁴, or B⁵;

B¹ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or6-membered heteroaryl of B′ is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyland (C₃-C₇)cycloalkyl;

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁴ is a 5-membered heteroaryl, 6-membered heteroaryl, or phenyl, whereinany 5-membered heteroaryl, 6-membered heteroaryl, or phenyl of B⁴ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R² is halogen, (C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² isoptionally substituted with one or more groups independently selectedfrom halogen, —OH and —O(C₁-C₆)alkyl;

each R^(3a) is independently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3b) group is halogen, —CN, or (C₁-C₆)alkyl and the remainingR^(3b) groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl;

one R^(3b)′ group is halogen, (C₁-C₆)alkyl, —CN, or (C₁-C₆)haloalkyl andthe remaining R^(3b)′ groups are independently selected from H,(C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

two R^(3c) groups attached to different non-adjacent carbon atoms oradjacent carbon atoms are combined to form a (C₁-C₄)alkyl linker or a(C₁-C₂)alkyl-O-(C₁-C₂)alkyl linker, wherein the (C₁-C₄)alkyl linker or(C₁-C₂)alkyl-O-(C₁-C₂)alkyl linker is optionally substituted with one ormore groups independently selected from halogen and (C₁-C₆)alkyl, andthe remaining R^(3c) groups are independently selected from H, halogenand (C₁-C₆)alkyl;

each R^(3d) group is independently selected from H, halogen,(C₁-C₆)alkyl, and —CN, wherein any (C₁-C₆)alkyl of R^(3d) is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl;

one R^(3e) group is halogen, —CN or (C₁-C₆)alkyl and the remainingR^(3e) groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl;

two R^(3f) groups attached to the same carbon atom are combined to forma (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linker is optionallysubstituted with one or more groups independently selected from halogenand (C₁-C₆)alkyl, and the remaining R^(3f) groups are independentlyselected from H, halogen and (C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R⁵ is R^(5a) or R^(5b);

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen, which —O-(C₁-C₂)alkyl-O- group is bonded totwo adjacent carbon atoms of any phenyl, 5-membered heteroaryl,6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or(C₃-C₈)cycloalkyl of R^(5a);

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

each R⁶ is independently H or (C₁-C₆)alkyl;

or a salt or pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier.

The invention also provides a compound of the invention or apharmaceutically acceptable salt thereof for use in medical therapy.

The invention also provides for a compound of the invention or apharmaceutically acceptable salt thereof for the treatment orprophylaxis of a respiratory disorder.

The invention provides for the use of a compound of the invention or apharmaceutically acceptable salt thereof for the preparation of amedicament for the treatment or prophylaxis of a respiratory disorder.

The invention also provides for a method for treating a respiratorydisorder in a mammal (e.g., a human) comprising, administering acompound of the invention or a pharmaceutically acceptable salt thereofto the mammal.

The invention also provides for a compound of the invention or apharmaceutically acceptable salt thereof for modulating TRPA1 activity.

In another embodiment, the invention provides for a method formodulating TRPA1 activity, comprising contacting TRPA1 with a compoundof the invention or a salt thereof.

In another embodiment, the invention provides for a compound of theinvention or a pharmaceutically acceptable salt thereof for thetreatment or prophylaxis of a disease or condition mediated by TRPA1activity. Within aspects of this embodiment, the disease or condition ispain, itch, an inflammatory disorder, an inner ear disorder, fever oranother disorder of thermoregulation, tracheobronchial or diaphragmaticdysfunction, a gastrointestinal or urinary tract disorder, chronicobstructive pulmonary disease, incontinence, or a disorder associatedwith reduced blood flow to the CNS or CNS hyl)oxia. Within certainaspects of this embodiment, the disease or condition is pain, arthritis,itch, cough, asthma, inflammatory bowel disease, or an inner eardisorder.

In another embodiment, the invention provides for the use of a compoundof the invention or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment or prophylaxis of adisease or condition that is mediated by TRPA1 activity. Within aspectsof this embodiment, the disease or condition is pain, itch, aninflammatory disorder, an inner ear disorder, fever or another disorderof thermoregulation, tracheobronchial or diaphragmatic dysfunction, agastrointestinal or urinary tract disorder, chronic obstructivepulmonary disease, incontinence, or a disorder associated with reducedblood flow to the CNS or CNS hyl)oxia. Within aspects of thisembodiment, the disease or condition is pain, arthritis, itch, cough,asthma, inflammatory bowel disease, or an inner ear disorder.

In another embodiment, the invention provides for a method for treatinga disease or condition mediated by TRPA1 activity in a mammal (e.g., ahuman), comprising administering a compound of the invention or apharmaceutically acceptable salt thereof to the mammal. Within certainaspects of this embodiment, the disease or condition is pain, itch, aninflammatory disorder, an inner ear disorder, fever or another disorderof thermoregulation, tracheobronchial or diaphragmatic dysfunction, agastrointestinal or urinary tract disorder, chronic obstructivepulmonary disease, incontinence, or a disorder associated with reducedblood flow to the CNS or CNS hyl)oxia. Within certain aspects of thisembodiment, the disease or condition is pain, arthritis, itch, cough,asthma, inflammatory bowel disease, or an inner ear disorder.

The invention also provides a compound of formula I or formula II or asalt thereof.

The invention also provides a compound of formula I or formula II or apharmaceutically acceptable salt thereof.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing a compound of formula I or formula II or asalt thereof.

The invention also provides an invention as described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise indicated, the following specific terms and phrasesused in the description and claims are defined as follows:

The term “moiety” refers to an atom or group of chemically bonded atomsthat is attached to another atom or molecule by one or more chemicalbonds thereby forming part of a molecule. For example, the variables R¹to R⁵ of formula I or II refer to moieties that are attached to the corestructure of formula I or II by a covalent bond.

In reference to a particular moiety with one or more hydrogen atoms, theterm “substituted” refers to the fact that at least one of the hydrogenatoms of that moiety is replaced by another substituent or moiety. Forexample, the term “lower alkyl substituted by halogen” refers to thefact that one or more hydrogen atoms of a lower alkyl (as defined below)is replaced by one or more halogen atoms (e.g., trifluoromethyl,difluoromethyl, fluoromethyl, chloromethyl, etc.).

The term “alkyl” refers to an aliphatic straight-chain or branched-chainsaturated hydrocarbon moiety having 1 to 20 carbon atoms. In particularembodiments the alkyl has 1 to 10 carbon atoms. In particularembodiments the alkyl has 1 to 6 carbon atoms.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group. Examples of alkoxy moieties include methoxy, ethoxy,isopropoxy, and tert-butoxy.

“Aryl” means a cyclic aromatic hydrocarbon moiety having a mono-, bi- ortricyclic aromatic ring of 6 to 16 carbon ring atoms. The aryl group canbe optionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, and the like, The term “aryl”also includes partially hydrogenated derivatives of the cyclic aromatichydrocarbon moiety provided that at least one ring of the cyclicaromatic hydrocarbon moiety is aromatic, each being optionallysubstituted. In one embodiment the aryl has 6 to 14 carbon ring atoms(i.e., (C₆-C₁₄)aryl). In another embodiment the aryl has 6 to 10 carbonring atoms (i.e., (C₆-C₁₀)aryl)

The term “heteroaryl” denotes an aromatic heterocyclic mono- or bicyclicring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatomsselected from N, O and S, the remaining ring atoms being carbon.Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl,indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl,benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, or quinoxalinyl.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

The term “haloalkyl” denotes an alkyl group wherein one or more of thehydrogen atoms of the alkyl group has been replaced by the same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or-propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

“Cycloalkyl” means a saturated or partially unsaturated carbocyclicmoiety having mono- or bicyclic (including bridged bicyclic) rings and 3to 10 carbon atoms in the ring. The cycloalkyl moiety can optionally besubstituted with one or more substituents. In particular embodimentscycloalkyl contains from 3 to 8 carbon atoms (i.e., (C₃-C₈)cycloalkyl).In other particular embodiments cycloalkyl contains from 3 to 6 carbonatoms (i.e., (C₃-C₆)cycloalkyl). Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl)derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, andcycloheptenyl). The cycloalkyl moiety can be attached in a“spirocycloakyl” fashion such as “spirocyclopropyl”:

“Heterocycle” refers to a 4, 5, 6 and 7-membered monocyclic or 7, 8, 9and 10-membered bicyclic (including bridged bicyclic) heterocyclicmoiety that is saturated or partially unsaturated, and has one or more(e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen andsulfur in the ring with the remaining ring atoms being carbon. When usedin reference to a ring atom of a heterocycle, a nitrogen or sulfur mayalso be in an oxidized form, and a nitrogen may be substituted with oneor more (C₁-C₆)alkyl or groups. The heterocycle can be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure and any of the ring atoms can be optionally substituted.Examples of such saturated or partially unsaturated heterocyclesinclude, without limitation, tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, and quinuclidinyl. The term the termheterocycle also includes groups in which a heterocycle is fused to oneor more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl,3H-indolyl, chromanyl, 2-azabicyclo[2.2.1]heptanyl,octahydroindolyl, ortetrahydroquinolinyl.

Unless otherwise indicated, the term “hydrogen” or “hydro” refers to themoiety of a hydrogen atom (—H) and not H₂.

Unless otherwise indicated, the term “a compound of the formula” or “acompound of formula” or “compounds of the formula” or “compounds offormula” refers to any compound selected from the genus of compounds asdefined by the formula (including any pharmaceutically acceptable saltor ester of any such compound if not otherwise noted).

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Saltsmay be formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,N-acetylcystein and the like. In addition, salts may be prepared by theaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, and magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable salts. Another embodiment providesnon-pharmaceutically acceptable salts of a compound of formula I or II,which can be useful as an intermediate for isolating or purifying acompound of Formula I or II. The compounds of the present invention canalso be present in the form of pharmaceutically acceptable esters (i.e.,the methyl and ethyl esters of the acids of Formula I or II to be usedas prodrugs). The compounds of the present invention can also besolvated, i.e. hydrated. The solvation can be effected in the course ofthe manufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compound of Formula Ior II.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”. Incertain embodiments the compound is enriched by at least about 90% byweight with a single diastereomer or enantiomer. In other embodimentsthe compound is enriched by at least about 95%, 98%, or 99% by weightwith a single diastereomer or enantiomer.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The term “a therapeutically effective amount” of a compound means anamount of compound that is effective to prevent, alleviate or amelioratesymptoms of disease or prolong the survival of the subject beingtreated. Determination of a therapeutically effective amount is withinthe skill in the art. The therapeutically effective amount or dosage ofa compound according to this invention can vary within wide limits andmay be determined in a manner known in the art. Such dosage will beadjusted to the individual requirements in each particular caseincluding the specific compound(s) being administered, the route ofadministration, the condition being treated, as well as the patientbeing treated. In general, in the case of oral or parenteraladministration to adult humans weighing approximately 70 Kg, a dailydosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1mg to 100 mg may be appropriate, although the lower and upper limits maybe exceeded when indicated. The daily dosage can be administered as asingle dose or in divided doses, or for parenteral administration, itmay be given as continuous infusion.

The term “pharmaceutically acceptable carrier” is intended to includeany and all material compatible with pharmaceutical administrationincluding solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and othermaterials and compounds compatible with pharmaceutical administration.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the compositions of the invention iscontemplated. Supplementary active compounds can also be incorporatedinto the compositions.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids or gases; thus, the compositions can takethe form of tablets, pills, capsules, suppositories, powders,enterically coated or other protected formulations (e.g. binding onion-exchange resins or packaging in lipid-protein vesicles), sustainedrelease formulations, solutions, suspensions, elixirs, aerosols, and thelike. The carrier can be selected from the various oils including thoseof petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly (when isotonic with the blood) for injectable solutions.For example, formulations for intravenous administration comprisesterile aqueous solutions of the active ingredient(s) which are preparedby dissolving solid active ingredient(s) in water to produce an aqueoussolution, and rendering the solution sterile. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, talc,gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodiumstearate, glycerol monostearate, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions may be subjected to conventional pharmaceutical additivessuch as preservatives, stabilizing agents, wetting or emulsifyingagents, salts for adjusting osmotic pressure, buffers and the like.Suitable pharmaceutical carriers and their formulation are described inRemington's Pharmaceutical Sciences by E. W. Martin. Such compositionswill, in any event, contain an effective amount of the active compoundtogether with a suitable carrier so as to prepare the proper dosage formfor proper administration to the recipient.

In the practice of the method of the present invention, an effectiveamount of any one of the compounds of this invention or a combination ofany of the compounds of this invention or a pharmaceutically acceptablesalt or ester thereof, is administered via any of the usual andacceptable methods known in the art, either singly or in combination.The compounds or compositions can thus be administered orally (e.g.,buccal cavity), sublingually, parenterally (e.g., intramuscularly,intravenously, or subcutaneously), rectally (e.g., by suppositories orwashings), transdermally (e.g., skin electroporation) or by inhalation(e.g., by aerosol), and in the form of solid, liquid or gaseous dosages,including tablets and suspensions. The administration can be conductedin a single unit dosage form with continuous therapy or in a single dosetherapy ad libitum. The therapeutic composition can also be in the formof an oil emulsion or dispersion in conjunction with a lipophilic saltsuch as pamoic acid, or in the form of a biodegradable sustained-releasecomposition for subcutaneous or intramuscular administration.

Compounds

In one aspect the present invention provides for compounds of formula Ias described herein below as a first embodiment of the invention(embodiment “E1”):

E1: A compound of formula I:

wherein:

(1) A is

B is B¹ and R⁵ is R^(5a);or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a); or

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a);

B is B¹, B², B³ or B⁴;

B¹ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or6-membered heteroaryl of B¹ is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyland (C₃-C₇)cycloalkyl;

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andwherein when B³ is pyrimidinyl which is attached to the remainder offormula I at the 4 and 6 positions of the pyrimidinyl, then R^(5a) isnot pyrrolidinyl or substituted pyrrolidinyl;

B⁴ is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any5-membered heteroaryl or 6-membered heteroaryl of B⁴ is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R^(I-) isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R² is halogen, (C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² isoptionally substituted with one or more groups independently selectedfrom halogen, —OH and —O(C₁-C₆)alkyl;

each R^(3a) is independently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3b) group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)groups are independently selected from H and (C₁-C₆)alkyl;

one R^(3b)′ group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)′groups are independently selected from H and (C₁-C₆)alkyl;

two R^(3c) groups attached to different non-adjacent carbon atoms arecombined to form a (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linkeris optionally substituted with one or more groups independently selectedfrom halogen and (C₁-C₆)alkyl, and the remaining R^(3c) groups areindependently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3d) group is halogen, (C₁-C₆)alkyl or CN and the remaining R^(3d)groups are independently selected from H, halogen and (C₁-C₆)alkyl,wherein any (C₁-C₆)alkyl of R^(3d) is optionally substituted with one ormore groups independently selected from halogen, —OH and —O(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R⁵ is R^(5a) or R^(5b);

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₇)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₇)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle ofR^(5b) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl, and wherein any 5-membered heterocycle of R^(5b)is substituted with one or more groups independently selected fromhalogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl;

or a pharmaceutically acceptable salt thereof.

Additional embodiments of the invention are set forth below.

E2: The compound according to E1 which is a compound of formula I′:

wherein:

(1) A is

B is B¹ and R⁵ is R^(5a); or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a).

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a);

B is B¹, B², B³ or B⁴;

B¹ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or6-membered heteroaryl of B¹ is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyland (C₃-C₇)cycloalkyl;

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andwherein when B³ is pyrimidinyl which is attached to the remainder offormula I at the 4 and 6 positions of the pyrimidinyl, then R^(5a) isnot pyrrolidinyl or substituted pyrrolidinyl;

B⁴ is a 5-membered heteroaryl or 6-membered heteroaryl, wherein any5-membered heteroaryl or 6-membered heteroaryl of B⁴ is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R² is halogen, (C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² isoptionally substituted with one or more groups independently selectedfrom halogen, —OH and —O(C₁-C₆)alkyl;

each R^(3a) is independently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3b) group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)groups are independently selected from H and (C₁-C₆)alkyl;

one R^(3b)′ group is halogen or (C₁-C₆)alkyl and the remaining R^(3b)′groups are independently selected from H and (C₁-C₆)alkyl;

two R^(3c) groups attached to different non-adjacent carbon atoms arecombined to form a (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linkeris optionally substituted with one or more groups independently selectedfrom halogen and (C₁-C₆)alkyl, and the remaining R^(3c) groups areindependently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3d) group is halogen, (C₁-C₆)alkyl or CN and the remaining R^(3d)groups are independently selected from H, halogen and (C₁-C₆)alkyl,wherein any (C₁-C₆)alkyl of R^(3d) is optionally substituted with one ormore groups independently selected from halogen, —OH and —O(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R⁵ is R^(5a) or R^(5b);

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₇)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₇)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6 or 7-membered heterocycle ofR^(5b) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl, and wherein any 5-membered heterocycle of R^(5b)is substituted with one or more groups independently selected fromhalogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl;

or a pharmaceutically acceptable salt thereof.

E3: The compound according to E1 or E2, wherein each R^(3a) isindependently H or F.

E4: The compound according to E1 or E2, wherein one R^(3a) is F and theremaining R^(3a) groups are H.

E5: The compound according to E1 or E2, wherein each R^(3a) is H.

E6: The compound according to any one of E1-E5, wherein R² is(C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl.

E7: The compound according to any one of E1-E5, wherein R² is —CH₃,—CH₂OH, —CHF₂, —CH₂OCH₃ or CN.

E8: The compound according to any one of E1-E5, wherein R² is —CH₃.

E9: The compound according to any one of E1-E8, wherein B¹ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E10: The compound according to any one of E1-E8, wherein B¹ is apyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E11: The compound according to any one of E1-E8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E12: The compound according to any one of E1-E8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E13: The compound according to any one of E1-E8, wherein B¹ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E14: The compound according to any one of E1-E8, wherein B¹ is apyrazolyl, wherein any pyrazolyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E15: The compound according to any one of E1-E8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E16: The compound according to any one of E1-E15, wherein one R^(3b)group is F, one R^(3b)′ group is F and the remaining R^(3b) groups andR^(3b)′groups are H.

E17: The compound according to any one of E1-E15, wherein

(1) the A group

is:

B is B² and R⁵ is R^(5b); and

(2) the A group

is:

B is B³ and R⁵ is R^(5a).

E18: The compound according to any one of E1-E15, wherein B² ispyridinyl, wherein any pyridinyl of B² is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl.

E19: The compound according to any one of E1-E15, wherein B²is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E20: The compound according to any one of E1-E19, wherein B³ ispyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl orpyrimidinyl of B³ is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and(C₃-C₇)cycloalkyl.

E21: The compound according to any one of E1-E19, wherein B³ is apyrimidinyl, wherein any pyrimidinyl of B³ is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E22: The compound according to any one of E1-E19, wherein B³ is:

wherein each R^(Z1) is independently selected from hydrogen halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E23: The compound according to any one of E1-E19, wherein B³ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E24: The compound according to any one of E1-E19, wherein B³ is apyrazolyl, wherein any pyrazolyl of B³ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E25: The compound according to any one of E1-E19, wherein B³ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E26: The compound according to any one of E1-E25, wherein one two R^(3c)groups attached to different non-adjacent carbon atoms are combined toform a —CH₂CH₂- linker and the remaining R^(3c) groups are each H.

E27: The compound according to any one of E1-E25, wherein the

A group

is:

B is B⁴ and R⁵ is R^(5a).

E28: The compound according to any one of E1-E27, wherein B⁴ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B⁴ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E29: The compound according to any one of E1-E27, wherein B⁴ is apyrimidinyl, wherein any pyrimidinyl of B⁴ is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E30: The compound according to any one of E1-E27, wherein B⁴ is:

wherein each R^(Z1) is independently selected from hydrogen halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E31: The compound according to any one of E1-E30, wherein one R^(3d)group is halogen or (C₁-C₆)alkyl and the remaining R^(3d) groups are H.

E32: The compound according to any one of E1-E30, wherein one R^(3d)group is methyl and the remaining R^(3d) groups are H.

E33: The compound according to any one of E1-E30, wherein the

A group

is:

B is B¹ and R⁵ is R^(5a).

E34: The compound of any one of E11, E12, E15, E19, E22, E25 or E30,wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, and (C₃-C₇)cycloalkyl.

E35: The compound of any one of E11, E12, E15, E19, E22, E25 or E30,wherein each R^(Z1) is independently selected from H, fluoro, chloro,methyl and cyclopropyl.

E36: The compound of any one of 12, 22 or 30, wherein each R^(Z1) is H.

E37: The compound according to any one of E1-E36, wherein R⁴ is H.

E38: The compound according to any one of E1-E37, wherein R¹ is a phenylor thiophenyl, wherein any phenyl or thiophenyl of R¹ is optionallysubstituted with one or more groups independently selected from halogen,—CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E39: The compound according to any one of E1-E37, wherein R¹ is a phenylor thiophenyl, wherein any phenyl or thiophenyl of R¹ is optionallysubstituted with one or more groups independently selected from halogenand —CN.

E40: The compound according to any one of E1-E37, wherein R¹ is a phenylor thiophenyl, wherein any phenyl or thiophenyl of R¹ is optionallysubstituted with one or more groups independently selected from fluoro,chloro and —CN.

E41: The compound according to any one of E1-E37, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E42: The compound according to any one of E1-E41, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and R^(5b) isphenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein anyphenyl, 6-membered heteroaryl or 6-membered heterocycle of R^(5b) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E43: The compound according to any one of E1-E41, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl; and R^(5b) is phenyl,6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl,6-membered heteroaryl or 6-membered heterocycle of R^(5b) is optionallysubstituted with one or more groups independently selected from(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E44: The compound according to any one of E1-E41, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyland —S(C₁-C₆)haloalkyl; and R^(5b) is phenyl, pyridinyl or piperidinyl,wherein any phenyl, pyridinyl or piperidinyl of R^(5b) is optionallysubstituted with one or more groups independently selected from(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E45: The compound according to any one of E1-E41, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl; and R^(5b) is phenyl,pyridinyl or piperidinyl, wherein any phenyl, pyridinyl or piperidinylof R^(5b) is optionally substituted with one or more groupsindependently selected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E46: The compound according to any one of E1-E41, wherein R^(5a) orR^(5b) is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a)or R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl,—S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E47: The compound according to any one of E1-E41, wherein R^(5a) orR^(5b) is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a)or R^(5b) is optionally substituted with one or more groupsindependently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E48: The compound according to any one of E1-E41, wherein R^(5a) orR^(5b) is phenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a)or R^(5b) is optionally substituted with one or more groupsindependently selected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E49: The compound according to any one of E1-E41, wherein R^(5a) is

E50: The compound according to any one of E1-E41, wherein R^(5b) is

E1A: The compound according to E1, wherein

A is

B is B¹ and R⁵ is R^(5a).

E2A: The compound according to E1, wherein

A is

B is B¹ and R⁵ is R^(5a).

E3A: The compound according to E1 which is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof.

E4A: The compound according to E1 which is a compound of formula Ia′:

or a pharmaceutically acceptable salt thereof.

E5A: The compound according to any one of E1A-E4A, wherein one R^(3a) isF and the remaining R^(3a) groups are H.

E6A: The compound according to any one of E1A-E4A, wherein each R^(3a)is H.

E7A: The compound according to any one of E1A-E6A, wherein R² is(C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl.

E8A: The compound according to any one of E1A-E6A, wherein R² is —CH₃,—CH₂OH, —CHF₂, —CH₂OCH₃ or CN.

E9A: The compound according to any one of E1A-E6A, wherein R² is —CH₃.

E 10A: The compound according to any one of E1A-E9A, wherein B¹ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E 11A: The compound according to any one of E1A-E9A, wherein B¹ is apyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E12A: The compound according to any one of E1A-E9A, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E13A: The compound according to any one of E1A-E9A, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E14A: The compound according to any one of E1A-E9A, wherein B¹ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E15A: The compound according to any one of E1A-E9A, wherein B¹ is apyrazolyl, wherein any pyrazolyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E16A: The compound according to any one of E1A-E9A, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E17A: The compound according to any one E12A, E13A or E14A, wherein eachR^(Z1) is independently selected from H, halogen, (C₁-C₆)alkyl, and(C₃-C₇)cycloalkyl.

E18A: The compound according to any one E12A, E1A or E14A, wherein eachR^(Z1) is independently selected from H, fluoro, chloro, methyl andcyclopropyl.

E19A: The compound according to E12A or E13A, wherein each R^(Z1) is H.

E20A: The compound according to any one of E1A-E19A, wherein R⁴ is H.

E21A: The compound according to any one of E1A-E20A, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E22A: The compound according to any one of E1A-E20A, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

E23A: The compound according to any one of E1A-E20A, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

E24A: The compound according to any one of E1A-E20A, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E25A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E26A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E27A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl.

E28A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyland —S(C₁-C₆)haloalkyl.

E29A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E30A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E31A: The compound according to any one of E1A-E24A, wherein lea isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E32A: The compound according to any one of E1A-E24A, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E33A: The compound according to any one of E1A-E24A, wherein R^(5a) is

E1B: The compound of E1 wherein:

A is

B is B² and R⁵ is R^(5b).

E2B: The compound of E1 wherein:

A is B is B² and le is R^(5b).

E3B: The compound according to E1 which is a compound of formula Ib:

or a pharmaceutically acceptable salt thereof.

E4B: The compound according to E1 which is a compound of formula Ib′:

or a pharmaceutically acceptable salt thereof.

E5B: The compound according to any one of E1B-E4B, wherein one R^(3b)group is F and the remaining R^(3b) groups are H.

E6B: The compound according to E2B or E4B, wherein the A group

E7B: The compound according to any one of E1B-E7B, wherein B² ispyridinyl, wherein any pyridinyl of B² is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl.

E8B: The compound according to any one of E1B-E7B, wherein B² is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E9B: The compound according to E8B, wherein each R^(Z1) is independentlyselected from H, halogen, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E10B: The compound according to EBB, wherein each R^(Z1) is H.

E11B: The compound according to any one of E1B-E10B, wherein R⁴ is H.

E12B: The compound according to any one of E1B-E11B, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E13B: The compound according to any one of E1B-E11B, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

E14B: The compound according to any one of E1B-E11B, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

E15B: The compound according to any one of E1B-E11B, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E16B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein anyphenyl, 6-membered heteroaryl or 6-membered heterocycle of R^(5b) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E17B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein anyphenyl, 6-membered heteroaryl or 6-membered heterocycle of R^(5b) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E18B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl orpiperidinyl of R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl,—S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E19B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl orpiperidinyl of R^(5b) is optionally substituted with one or more groupsindependently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E20B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl, pyridinyl, or piperidinyl, wherein any phenyl, pyridinyl orpiperidinyl of R^(5b) is optionally substituted with one or more groupsindependently selected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E21B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E22B: The compound according to any one of E1B-E15B, wherein R^(5b) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E23B: The compound according to any one of EIB-E15B, wherein R^(5b) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E24B: The compound according to any one of EIB-E15B, wherein R^(5b) is

E1C: The compound of E1 wherein:

A is

B is B³ and R⁵ is R^(5a).

E2C: The compound of E1 wherein:

A is

B is B³ and R⁵ is R^(5a).

E3C: The compound according to E1 which is a compound of formula Ic:

or a pharmaceutically acceptable salt thereof.

E4C: The compound according to E1 which is a compound of formula Ic′:

or a pharmaceutically acceptable salt thereof.

E5C: The compound according to any one of E1C-E4C, wherein one R^(3b)′group is F and the remaining R^(3b)′ groups are H.

E6C: The compound according to E2C or E4C, wherein the A group

E7C: The compound according to any one of E1C-E6C, wherein B³ ispyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl orpyrimidinyl of B³ is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and(C₃-C₇)cycloalkyl.

E8C: The compound according to any one of E1C-E6C, wherein B³ is apyrimidinyl, wherein any pyrimidinyl of B³ is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E9C: The compound according to any one of E1C-E6C, wherein B³ is:

wherein each R^(Z1) is independently selected from hydrogen halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E10C: The compound according to any one of E1C-E6C, wherein B³ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E11C: The compound according to any one of E1C-E6C, wherein B³ is apyrazolyl, wherein any pyrazolyl of B³ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E12C: The compound according to any one of E1C-E6C, wherein B³ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E13C: The compound according to E9C or E12C, wherein each R^(Z1) isindependently selected from H, halogen, (C₁-C₆)alkyl, and(C₃-C₇)cycloalkyl.

E14C: The compound according to E9C or E12C, wherein each R^(Z1) isindependently selected from H, fluoro, chloro, methyl and cyclopropyl.

E15C: The compound according to E9C, wherein each R^(Z1) is H.

E16C: The compound according to any one of E1C-E15C, wherein R⁴ is H.

E17C: The compound according to any one of E1C-E16C, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E18C: The compound according to any one of E1C-E16C, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

E19C: The compound according to any one of E1C-E16C, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

E20C: The compound according to any one of E1C-E16C, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E21C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E22C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E23C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl.

E24C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyland —S(C₁-C₆)haloalkyl.

E25C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E26C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E27C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E28C: The compound according to any one of E1C-E20C, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E29C: The compound according to any one of E1C-E20C, wherein R^(5a) is

E1D: The compound of E1 wherein:

A is

B is B⁴ and R⁵ is R^(5a).

E2D: The compound of E1 wherein:

A is

B is B⁴ and R⁵ is R^(5a).

E3D: The compound according to E1 which is a compound of formula Id:

or a pharmaceutically acceptable salt thereof

E4D: The compound according to E1 which is a compound of formula Id′:

or a pharmaceutically acceptable salt thereof.

E5D: The compound according to any one of E1D-E4D, wherein two R^(3c)groups attached to different non-adjacent carbon atoms are combined toform a —CH₂CH₂— linker and the remaining R^(3c) groups are each H.

E6D: The compound according to E2D or E4D, wherein the A group

E7D: The compound according to any one of E1D-E6D, wherein B⁴ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B⁴ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E8D: The compound according to any one of E1D-E6D, wherein B⁴ is apyrimidinyl, wherein any pyrimidinyl of B⁴ is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E9D: The compound according to any one of E1D-E6D, wherein B⁴ is:

wherein each R^(Z1) is independently selected from hydrogen halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E10D: The compound according to E9D, wherein each R^(Z1) isindependently selected from H, halogen, (C₁-C₆)alkyl, and(C₃-C₇)cycloalkyl.

E11D: The compound according to E9D, wherein each R^(Z1) isindependently selected from H, fluoro, chloro, methyl and cyclopropyl.

E12D: The compound according to E9D, wherein each R^(Z1) is H.

E13D: The compound according to any one of E1D-E12D, wherein R⁴ is H.

E14D: The compound according to any one of E1D-E13D, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E15D: The compound according to any one of E1D-E13D, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

E16D: The compound according to any one of E1D-E13D, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

E17D: The compound according to any one of E1D-E13D, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E18D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E19D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E20D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl.

E21D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyland —S(C₁-C₆)haloalkyl.

E22D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E23D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E24D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E25D: The compound according to any one of E1D-E17D, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E26D: The compound according to any one of E1D-E17D, wherein R^(5a) is

E1E: The compound according to E1, wherein

A is

B is B¹ and R⁵ is R^(5a).

E2E: The compound according to E1, wherein

A is

B is B¹ and R⁵ is R^(5a).

E3E: The compound according to E1 which is a compound of formula Ie:

or a pharmaceutically acceptable salt thereof.

E4E: The compound according to E1 which is a compound of formula Ie′ :

or a pharmaceutically acceptable salt thereof.

E5E: The compound according to any one of E1E-E5E, wherein one R^(3d)group is halogen or (C₁-C₆)alkyl and the remaining R^(3d) groups are H.E5E:

E6E: The compound according to any one of E1E-E5E, wherein one R^(3d)group is halogen and the remaining R^(3d) groups are H.

E7E: The compound according to any one of E1E-E5E, wherein one R^(3d)(C₁-C₆)alkyl and the remaining R^(3d) groups are H.

E8E: The compound according to any one of E1E-E5E, wherein one R^(3d)group is methyl and the remaining R^(3d) groups are H.

E9E: The compound according to E2E or E4E, wherein the A group

E10E: The compound according to any one of E1E-E9E, wherein B¹ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E11E: The compound according to any one of E1E-E9E, wherein B¹ is apyridinyl or pyrimidinyl, wherein any pyridinyl or pyrimidinyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E12E: The compound according to any one of E1E-E9E, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E13E: The compound according to any one of E1E-E9E, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E14E: The compound according to any one of E1E-E9E, wherein B¹ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E15E: The compound according to any one of E1E-E9E, wherein B¹ is apyrazolyl, wherein any pyrazolyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E16E: The compound according to any one of E1E-E9E, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

E17E: The compound according to E12E, E13E or E16E, wherein each R^(Z1)is independently selected from H, halogen, (C₁-C₆)alkyl, and(C₃-C₇)cycloalkyl.

E18E: The compound according to E12E, E13E or E16E, wherein each R^(Z1)is independently selected from H, fluoro, chloro, methyl andcyclopropyl.

E19E: The compound according to E12E or E13E, wherein each R^(Z1) is H.

E20E: The compound according to any one of E1E-E19E, wherein R⁴ is H.

E21E: The compound according to any one of E1E-E20E, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

E22E: The compound according to any one of E1E-E20E, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

E23E: The compound according to any one of E1E-E20E, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

E24E: The compound according to any one of E1E-E20E, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

E25E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

E26E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

E27E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN,(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyland —S(C₁-C₆)haloalkyl.

E28E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyland —S(C₁-C₆)haloalkyl.

E29E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl, whereinany phenyl, pyridinyl, piperidinyl, cyclohexenyl or cyclohexanyl ofR^(5a) is optionally substituted with one or more groups independentlyselected from —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E30E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl.

E31E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

E32E: The compound according to any one of E1E-E24E, wherein R^(5a) isphenyl or pyridinyl, wherein any phenyl or pyridinyl of R^(5a) isoptionally substituted with one or more groups independently selectedfrom —CF₃, —SCF₃, —OCF₃ or cyclopropyl.

E33E: The compound according to any one of E1E-E24E, wherein R^(5a) is

In another embodiment, compounds of formula I or formula II are selectedfrom the compound in the Table 1 below or a salt or a pharmaceuticallyacceptable salt thereof.

TABLE 1 Example Chemical Name via Number ChemDraw Structure 1 (S)-1-(4-fluorophenylsulfonyl)-2- methyl-N-((6-(6- (trifluoromethyl)pyridin-3-yl)pyrimidin-4- yl)methyl)pyrrolidine-2- carboxamide

2 (S)-1-(4- fluorophenylsulfonyl)-2- methyl-N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)azetidine-2-carboxamide

4 (2S,4S)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

3 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

5 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethyl)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

6 (2S,4R)-4-fluoro-1-(3- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethyl)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

14 (S)-1-(4- fluorophenylsulfonyl)-2- methyl-N-((6-(5-(trifluoromethyl)pyridin-2- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

7 (R)-1-(4- fluorophenylsulfonyl)-2- (hydroxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

9 (2S,4R)-4-fluoro-N-((5′- fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)- 1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

8 (2S,4R)-4-fluoro-N-((5- fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)- 1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

17 (2S,4R)-N-((3-cyclopropyl- 1-(6- (trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4- yl)methyl)-4-fluoro-1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

15 (2S,4R)-N-((3-chloro-1-(6- (trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4- yl)methyl)-4-fluoro-1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

16 (2S,4R)-N-((3-chloro-1-(4- (trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methyl)-4- fluoro-1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

18 (2S,4R)-N-((3-chloro-1-(4- (trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methyl)-1- (4-cyanophenylsulfonyl)-4-fluoropyrrolidine-2- carboxamide

19 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-2- methyl-N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

10 (2S,4R)-N-((6-(4- cyclopropylphenyl) pyrimidin-4-yl)methyl)-4-fluoro-1-(4- fluorophenylsulfonyl) pyrrolidine-2-carboxamide

11 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethyl)piperidin- 1-yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

20 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-2- methyl-N-((6-(4-(trifluoromethyl)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

21 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethoxy)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

22 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((2-methyl-6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

23 (2S,4R)-N-((6-(6- cyclopropylpyridin-3- yl)pyrimidin-4-yl)methyl)-4-fluoro-1-(4- fluorophenylsulfonyl) pyrrolidine-2-carboxamide

24 (2S,4R)-1-(5- chlorothiophen-2- ylsulfonyl)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin- 3-yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

25 (2S,4R)-1-(3,4- difluorophenylsulfonyl)-4- fluoro-N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

26 (2S,4R)-1-(3,4- difluorophenylsulfonyl)-4- fluoro-N-((6-(4-(trifluoromethyl)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

27 (2S,4R)-4-fluoro-1-(5- fluoropyridin-3-ylsulfonyl)- N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

28 (2S,4R)-4-fluoro-1-(5- fluoropyridin-3-ylsulfonyl)- N-((6-(4-(trifluoromethyl)phenyl) pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

29 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethylthio) phenyl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

12 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethyl)cyclohex- 1-enyl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

13 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-((1s,4R)-4-(trifluoromethyl) cyclohexyl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

13 (2S,4R)-4-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-((1r,4S)-4-(trifluoromethyl) cyclohexyl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

30 (R)-1-(4- fluorophenylsulfonyl)-2- (methoxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

31 (S)-2-(difluoromethyl)-1-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

32 (R)-2-cyano-1-(4- fluorophenylsulfonyl)-N- ((4-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

35 (2R,3S)-3-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

33 (1R,3S,4S)-2-(4- fluorophenylsulfonyl)-N- ((6-(4-(trifluoromethyl)phenyl) pyrimidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3- carboxamide

34 (1R,3S,4S)-2-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptane- 3-carboxamide

36 (2R,3R)-3-fluoro-1-(4- fluorophenylsulfonyl)-N- ((6-(6-(trifluoromethyl)pyridin-3- yl)pyrimidin-4- yl)methyl)pyrrolidine-2-carboxamide

37 (2S,4R)-4-fluoro-N-((5- fluoro-4-(4- (trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)- 1-(4- fluorophenylsulfonyl)pyrrolidine-2-carboxamide

In another aspect the present invention provides for compounds offormula II as described herein below as a second embodiment of theinvention (embodiment “EE1”):

EE 1. A compound of formula II:

wherein:

(1) A is

B is B¹ and R⁵ is R^(5a); or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a); or

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a); or

(6) A is

B is B⁵ and R⁵ is R^(5a); or

(7) A is

B is B³ and R⁵ is R^(5a);

B is B¹, B², B³, B⁴, or B⁵;

B¹ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or6-membered heteroaryl of B¹ is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyland (C₃-C₇)cycloalkyl;

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of Formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁴ is a 5-membered heteroaryl, 6-membered heteroaryl, or phenyl, whereinany 5-membered heteroaryl, 6-membered heteroaryl, or phenyl of B⁴ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R² is halogen, (C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² isoptionally substituted with one or more groups independently selectedfrom halogen, —OH and —O(C₁-C₆)alkyl;

each R^(3a) is independently selected from H, halogen and (C₁-C₆)alkyl;

one R^(3b) group is halogen, —CN, or (C₁-C₆)alkyl and the remainingR^(3b) groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl;

one R^(3b)′ group is halogen, (C₁-C₆)alkyl, —CN, or (C₁-C₆)haloalkyl andthe remaining R^(3b)′ groups are independently selected from H,(C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

two R^(3c) groups attached to different non-adjacent carbon atoms oradjacent carbon atoms are combined to form a (C₁-C₄)alkyl linker or a(C₁-C₂)alkyl-O-(C₁-C₂)alkyl linker, wherein the (C₁-C₄)alkyl linker or(C₁-C₂)alkyl-O-(C₁-C₂)alkyl linker is optionally substituted with one ormore groups independently selected from halogen and (C₁-C₆)alkyl, andthe remaining R^(3c) groups are independently selected from H, halogenand (C₁-C₆)alkyl;

each R^(3d) group is independently selected from H, halogen,(C₁-C₆)alkyl, and —CN, wherein any (C₁-C₆)alkyl of le is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl;

one R^(3e) group is halogen, —CN or (C₁-C₆)alkyl and the remainingR^(3e) groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl;

two R^(3f) groups attached to the same carbon atom are combined to forma (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linker is optionallysubstituted with one or more groups independently selected from halogenand (C₁-C₆)alkyl, and the remaining R^(3f) groups are independentlyselected from H, halogen and (C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R⁵ is R^(5a) or R^(5b);

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo and —O—(C₁-C₂)alkyl-O— optionally substitutedwith one or more halogen, which —O—(C₁-C₂)alkyl-O— group is bonded totwo adjacent carbon atoms of any phenyl, 5-membered heteroaryl,6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or(C₃-C₈)cycloalkyl of R^(5a);

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7 or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

each R⁶ is independently H or (C₁-C₆)alkyl;

or a salt thereof.

Additional embodiments of the invention are set forth below.

EE2. The compound of embodiment EE1, wherein:

(1) A is

B is B¹ and R⁵ is R^(5a); or

(2) A is

B is B² and R⁵ is R^(5b); or

(3) A is

B is B³ and R⁵ is R^(5a) or

(4) A is

B is B⁴ and R⁵ is R^(5a); or

(5) A is

B is B¹ and R⁵ is R^(5a); or

(6) A is

B is B⁵ and R⁵ is R^(5a); or

(7) A is

B is B³ and R⁵ is R.

EE3. The compound of embodiment EE1 or embodiment EE2, wherein eachR^(3a) is independently H or F.

EE4. The compound of embodiment EE1 or embodiment EE2, wherein oneR^(3a) is F and the remaining R^(3a) groups are H.

EE5. The compound of embodiment EE1 or embodiment EE2, wherein eachR^(3a) is H.

EE6. The compound of any one of embodiments EE1-EE5, wherein R² is(C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl.

EE7. The compound of any one of embodiments EE1-EE5, wherein R² is —CH₃,—CH₂OH, —CHF₂, —CH₂OCH₃ or CN.

EE8. The compound of any one of embodiments EE1-EE5, wherein R² is —CH₃.

EE9. The compound of any one of embodiments EE1-EE8, wherein B¹ is apyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl,triazolyl, pyridinyl or pyrimidinyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE10. The compound of any one of embodiments EE1-EE8, wherein B¹ is apyridinyl or pyrimidinyl wherein any pyridinyl or pyrimidinyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE11. The compound of any one of embodiments EE1-EE8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE12. The compound of any one of embodiments EE1-EE8 1-8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE13. The compound of any one of embodiments EE1-EE8, wherein B¹ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B¹ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE14. The compound of any one of embodiments EE1-EE8, wherein B¹ is apyrazolyl, wherein any pyrazolyl of B¹ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE15. The compound of any one of embodiments EE1-EE8, wherein B¹ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE16. The compound of any one of embodiments EE1-EE15, wherein oneR^(3b) group is F and the remaining R^(3b) groups are H, and one R^(3b)′group is F and the remaining R^(3b)′groups are H.

EE16a. The compound of any one of embodiments EE1-EE15, wherein oneR^(3b) group is halogen, —CN, or (C₁-C₆)alkyl and the remaining R^(3b)groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl, and one R^(3b)′ group is halogen, (C₁-C₆)alkyl, —CN,or (C₁-C₆)haloalkyl and the remaining R^(3b)′ groups are independentlyselected from H, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

EE16b. The compound of any one of embodiments EE1-EE15, wherein oneR^(3b) group is halogen or (C₁-C₆)alkyl and the remaining R^(3b) groupsare independently selected from H and (C₁-C₆)alkyl, and one R^(3b)′group is halogen, (C₁-C₆)alkyl, —CN, or (C₁-C₆)haloalkyl and theremaining R^(3b)′ groups are independently selected from H and(C₁-C₆)alkyl.

EE17. The compound of any one of embodiments EE1-EE15, wherein

(1) the A group

is:

B is B² and R⁵ is R^(5b);

(2) the A group

is:

B is B³ and R⁵ is R^(5a); and

(3) the A group

is:

B is B⁵ and R⁵ is R^(5a).

EE17a. The compound of any one of embodiments EE1-EE15, wherein

(1) the A group

is:

B is B² and R⁵ is R^(5b);

(2) the A group

is:

B is B³ and R⁵ is R^(5a); and

(3) the A group

is:

B is B⁵ and R⁵ is R^(5a).

EE18. The compound of any one of embodiments EE1-EE17, wherein B² ispyridinyl, wherein any pyridinyl of B² is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-memberedheteroaryl is optionally substituted with one or more (C₁-C₆)alkyl or(C₁-C₆)haloalkyl.

EE18a. The compound of any one of embodiments EE1-EE17, wherein B² ispyridinyl, wherein any pyridinyl of B² is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, and6-membered heteroaryl, wherein any 6-membered heteroaryl is optionallysubstituted with one or more (C₁-C₆)alkyl or (C₁-C₆)haloalkyl.

EE19. The compound of any one of embodiments EE1-EE17, wherein B² is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with(C₁-C₆)alkyl or (C₁-C₆)haloalkyl.

EE20. The compound of any one of embodiments EE1-EE19, wherein B³ ispyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl orpyrimidinyl of B³ is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, —CN, and NR⁶ ₂.

EE21. The compound of any one of embodiments EE1-EE19, wherein B³ is apyrimidinyl, wherein any pyrimidinyl of B³ is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, and NR⁶ ₂.

EE22. The compound of any one of embodiments EE1-EE19 wherein B³ is:

wherein each R^(Z1) is independently selected from hydrogen, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, and NR⁶ ₂.

EE23. The compound of any one of embodiments EE1-EE19, wherein B³ is apyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE24. The compound of any one of embodiments EE1-EE19, wherein B³ is apyrazolyl, wherein any pyrazolyl of B³ is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE25. The compound of any one of embodiments EE1-EE19, wherein B³ is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE26. The compound of any one of embodiments EE1-EE25, wherein twoR^(3c) groups attached to different non-adjacent carbon atoms ordifferent adjacent carbon atoms are combined to form a —CH₂, —CH₂CH₂— ora CH₂OCH₂— linker, wherein the —CH₂—, —CH₂CH₂— or a CH₂OCH₂— linker isoptionally substituted with one or more independent halogen groups andthe remaining R^(3c) groups are each H.

EE27. The compound of any one of embodiments EE1-EE25, wherein the Agroup

is:

B is B⁴ and R⁵ is R^(5a).

EE27a. The compound of any one of embodiments EE1-EE25, wherein the Agroup

is:

B is B⁴ and R⁵ is R^(5a).

EE28. The compound of any one of embodiments EE1-EE27, wherein B⁴ is apyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl wherein anypyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl of B⁴ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE29. The compound of any one of embodiments EE1-EE27, wherein B⁴ is apyrimidinyl, wherein any pyrimidinyl of B⁴ is optionally substitutedwith one or more groups independently selected from halogen, —CN,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE30. The compound of any one of embodiments EE1-EE27, wherein B⁴ is:

wherein each R^(Z1) is independently selected from hydrogen, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE30a. The compound of any one of embodiments EE1-EE27, wherein B⁴ is:

wherein each R^(Z1) is independently selected from hydrogen, halogen,—CN, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.

EE31. The compound of any one of embodiments EE1-EE30 wherein one R^(3d)group is halogen or (C₁-C₆)alkyl and the remaining R^(3d) groups are H.

EE32. The compound of any one of embodiments EE1-EE30 wherein one R^(3d)group is methyl and the remaining R^(3d) groups are H.

EE33. The compound of any one of embodiments EE1-EE30, wherein the Agroup

is:

B is B¹ and R⁵ is R^(5a).

EE33a. The compound of any one of embodiments EE1-EE30, wherein the Agroup

is:

B is B^(l)and R⁵ is R^(5a).

EE34. The compound of any one of embodiments EE11, EE12, EE15, EE19,EE22, EE25 or EE30, wherein each R^(Z1) is independently selected fromH, halogen, (C₁-C₆)alkyl, and (C₃-C₇)cycloalkyl.

EE35. The compound of any one of embodiments EE11, EE12, EE15, EE19,EE22, EE25 or EE30, wherein each R^(Z1) is independently selected fromH, fluoro, chloro, methyl, O(CH₃), —CN, (trifluoromethyl)pyrimidin-5-yl,—NH(CH₃), 2-methoxyethoxy, and cyclopropyl.

EE35a. The compound of any one of embodiments EE11, EE12, EE15, EE19,EE22, EE25 or EE30, wherein each R^(Z1) is independently selected fromH, fluoro, chloro, methyl, trifluoromethyl, —O(CH₃), —CN,2-(trifluoromethyl)pyrimidin-5-yl, 2-(trifluoromethyl)pyrinin-5-yl,—NH(CH₃), 2-methoxyethoxy, and cyclopropyl.

EE36. The compound of any one of embodiments EE12, EE22 or EE30, whereineach R^(Z1) is H.

EE37. The compound of any one of embodiments EE1-EE36, wherein R⁴ is H.

EE38. The compound of any one of embodiments EE1-EE37, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

EE39. The compound of any one of embodiments EE1-EE37, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen and —CN.

EE40. The compound of any one of embodiments EE1-EE37, wherein R¹ is aphenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN.

EE41. The compound of any one of embodiments EE1-EE37, wherein R¹ is4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl,3,4,-difluorophenyl or 3-fluoropyridin-5-yl.

EE42. The compound of any one of embodiments EE1-EE41, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen; and R^(5b) is phenyl, 6-membered heteroaryl or6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or6-membered heterocycle of R^(5b) is optionally substituted with one ormore groups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl optionally substituted with oneor more halogen, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH,—S(C₁-C₆)alkyl, —S(C₁-C₆)haloalkyl, and NR⁶ ₂.

EE42a. The compound of any one of embodiments EE1-EE41, wherein R^(5a)is phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-memberedheterocycle or (C₆)cycloalkyl of R^(5a) is optionally substituted withone or more groups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen, which —O—(C₁-C₂)alkyl-O- is bonded to twoadjacent atoms of any R^(5a) group ; and R^(5b) is phenyl, 6-memberedheteroaryl or 6-membered heterocycle, wherein any phenyl, 6-memberedheteroaryl or 6-membered heterocycle of R^(5b) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl optionallysubstituted with one or more halogen, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl, —S(C₁-C₆)haloalkyl, and NR⁶ ₂.

EE43. The compound of any one of embodiments EE1-EE41, wherein R^(5a) isphenyl, 6-membered heteroaryl, 6-membered heterocycle or (C₆)cycloalkyl,wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or(C₆)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl; and R^(5b) is phenyl,6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl,6-membered heteroaryl or 6-membered heterocycle of R^(5b) is optionallysubstituted with one or more groups independently selected from(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —O(C₁-C₆)haloalkyl and—S(C₁-C₆)haloalkyl.

EE44. The compound of any one of embodiments EE1-EE41, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, orbicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl,cyclohexanyl, or bicyclo[2.2.2]octanyl of R^(5a) is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen; and R^(5b) is phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or8-azabicyclo[3.2.1]octan-8-yl, wherein any phenyl, pyridinyl,piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyloptionally substituted with one or more halogen, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl, —S(C₁-C₆)haloalkyl, and NR⁶ ₂.

EE44. The compound of any one of embodiments EE1-EE41, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, orbicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl,cyclohexanyl, or bicyclo[2.2.2]octanyl of R^(5a) is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen, which —O—(C₁-C₂)alkyl-O- is bonded to twoadjacent atoms of any R^(5a) group; and R^(5b) is phenyl, pyridinyl,piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein anyphenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyloptionally substituted with one or more halogen, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl, —S(C₁-C₆)haloalkyl, and NR⁶ ₂.

EE45. The compound of any one of embodiments EE1-EE41, wherein R^(5a) isphenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, orbicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl,cyclohexanyl, or bicyclo[2.2.2]octanyl of R^(5a) is optionallysubstituted with one or more groups independently selected from —F,—CHF₂, —CF₃, —SCF₃, —OCHF₂, —OCF₃, oxo, —O—CF₂—O—, —OCH₂CH₂OCH₃,cyclopropyl, or spirocyclopropyl; and R^(5b) is phenyl, pyridinyl,piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein anyphenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R^(5b) isoptionally substituted with one or more groups independently selectedfrom —F, —CHF₂, —CF₃, —SCF₃, —OCH₃, —OCHF₂, —OCF₃, —OH, —NH₂, —NHCH₃,cyclopropyl, or 2,2-difluoro-spirocyclopropyl.

EE46. The compound of any one of embodiments EE1-EE41, wherein R^(5a) orR^(5b) is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinylwherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl ofR^(5a) or R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl,—S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl.

EE47. The compound of any one of embodiments EE1-EE41, wherein R^(5a) orR^(5b) is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinylwherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl ofR^(5a) or R^(5b) is optionally substituted with one or more groupsindependently selected from (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—O(C₁-C₆)haloalkyl and —S(C₁-C₆)haloalkyl.

EE48. The compound of any one of embodiments EE1-EE41, wherein R^(5a) orR^(5b) is _(p) henyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinylwherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl ofR^(5a) or R^(5b) is optionally substituted with one or more groupsindependently selected from —F, —CF₃, —OCF₃ or cyclopropyl.

EE49. The compound of any one of embodiments EE1-EE41, wherein R^(5a) is

EE50. The compound of any one of embodiments EE1-EE41, wherein R^(5b) is

EE51. The compound according to embodiment EE1, which is:

or a salt or a pharmaceutically acceptable salt thereof.

EE52. The compound according to embodiment EE1, which are selected fromthe compound in the Table 2 below or a salt or a pharmaceuticallyacceptable salt thereof:

TABLE 2 Example Number Chemical Name via ChemDraw Structure  38(2R,3S)-N-[[2-cyano-5-[2- (trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 39 (2S,5R)-1-(4- fluorophenyl)sulfonyl-5-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

 40 (2S,4S)-4-fluoro-4- (fluoromethyl)-1-(4-fluorophenyl)sulfonyl-N-[[6-[6- (trifluoromethyl)-3-pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2- carboxamide

 41 (2S,5S)-1-(4- fluorophenyl)sulfonyl-5-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

 42 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[2-(trifluoromethyl)pyrimidin-5- yl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide

 43 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- methyl-6-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

 44 (2S,4R)-4-fluoro-N-[[3-fluoro-5- [2-methoxy-6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 45 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[6-(trifluoromethyl)pyridazin-3- yl]phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide

 46 (2S)-4-fluoro-1-(4- fluorophenyl)sulfonyl-4-methyl- N-[[6-[4-(trifluoromethoxy)phenyl] pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

 47 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide

 48 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6- methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]- 2-pyridyl]methyl]pyrrolidine-2-carboxamide

 49 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-fluoro-4-[5-(trifluoromethyl)-2- pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

 50 (2S,4R)-N-[[3-cyano-1-[4- (trifluoromethyl)phenyl]pyrazol-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 51 5-fluoro-2-(4- fluorophenyl)sulfonyl-N-[[6-[6- (trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2- azabicyclo[2.2.1]heptane-3-carboxamide

 52 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide

 53 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]- 2-pyridyl]methyl]pyrrolidine-2-carboxamide

 54 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]methyl]pyrrolidine-2- carboxamide

 55 (2R,3S)-N-[[6-[4- (difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-3-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 56 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]pyrrolidine-2-carboxamide

 57 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[2- hydroxy-4-(trifluoromethyl)phenyl]-4- pyridyl]methyl]pyrrolidine-2- carboxamide

 58 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[5-(trifluoromethyl)pyrazin-2- yl]pyrazol-4- yl]methyl]pyrrolidine-2-carboxamide

 59 (2S,4R)-N-[[6-[4- (difluoromethyl)-3-fluoro-phenyl]pyrimidin-4-yl]methyl]-4- fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 60 (2S,4R)-N-[[2-chloro-6-[6- (difluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 61 (2S,4R)-N-[[2,6-bis[2- (trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 62 (2S,4R)-N-[[2-chloro-6-[2- (trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 63 (2S,4R)-N-[[6-[4- (difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 64 (2S,4R)-N-[[6-[4- (difluoromethoxy)phenyl] pyrimidin-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl- pyrrolidine-2-carboxamide

 65 (2S,4R)-4-fluoro-N-[[5-fluoro-4- [5-fluoro-6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 66 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-4-[4-(trifluoromethoxy)-1- piperidyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

 67 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[5-(trifluoromethyl)pyrazin-2-yl]-4- pyridyl]methyl]pyrrolidine-2-carboxamide

 68 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]pyrrolidine-2-carboxamide

 69 (2S,4R)-N-[[4-(2,2-difluoro-6- azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 70 (2S,4R)-N-[[5-cyano-4-[4- (trifluoromethyl)phenyl]-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 71 (2S,4R)-N-[[5-cyano-4-[6- (trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 72 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)-2-pyridyl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide

 73 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

 74 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)-2- piperidyl]phenyl]methyl]pyrrolidine-2-carboxamide

 75 (2S,4R)-N-[[3-[5- (difluoromethyl)-2-pyridyl]-5-fluoro-phenyl]methyl]-4-fluoro-1- (4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 76 (2S,4R)-N-[[3-[6- (difluoromethoxy)-3-pyridyl]-5-fluoro-phenyl]methyl]-4-fluoro-1- (4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 77 (2S,4R)-N-[[4-[4- (difluoromethoxy)phenyl]-5-fluoro-2-pyridyl]methyl]-4- fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 78 (2S,4R)-N-[[5-cyano-2-[4- (trifluoromethyl]phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 79 (2S,4R)-N-[[5-cyano-2-[6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 80 (6S)-5-(4-fluorophenyl)sulfonyl- N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-5- azaspiro[2,4]heptane-6- carboxamide

 81 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[6-(trifluoromethyl)-3-pyridyl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide

 82 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)pyrazin-2-yl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide

 83 (2S,4R)-N-[[2,6-bis[6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 84 (2S,4R)-N-[[2-chloro-6-[6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 85 (2S,4R)-4-fluoro-N-[[3-fluoro-5- [2-oxo-4-(trifluoromethyl)-1-pyridyl]phenyl]methyl]-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 86 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[4-(trifluoromethyl)pyrazol-1- yl]phenyl]methyl]pyrrolidine-2- carboxamide

 87 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[3-(trifluoromethyl)pyrazol-1- yl]phenyl]methyl]pyrrolidine-2- carboxamide

 88 (2S,4R)-N-[[4-[4- (difluoromethyl)phenyl]-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 89 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[6-(trifluoromethyl)pyridazin-3- yl]phenyl]methyl]pyrrolidine-2-carboxamide

 90 (2S,4R)-N-[[3-[5- (difluoromethyl)pyrazin-2-yl]-5-fluoro-phenyl]methyl]-4-fluoro-1- (4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 91 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]pyrrolidine-2-carboxamide

 92 (2S,4R)-N-[[6-(2,2-difluoro-1,3- benzodioxol-5-yl)pyrimidin-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 93 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[3- fluoro-4-(trifluoromethyl)phenyl] pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

 94 (2S,4R)-N-[[3-[6- (difluoromethyl)-3-pyridyl]-5-fluoro-phenyl]methyl]-4-fluoro-1- (4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

 95 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)-2- pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

 96 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-methyl-4-[6-(trifluoromethyl)-3- pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

 97 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4- fluoro-3-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]methyl]pyrrolidine-2- carboxamide

 98 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]methyl]pyrrolidine-2- carboxamide

 99 (2S,3aS,6aR)-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethyl)phenyl]pyrimidin- 4-yl]methyl]-2,3,3a,4,6,6a-hexahydrofuro[3,4-b]pyrrole-2- carboxamide

100 (2S,3aR,6aS)-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethyl)phenyl][pyrimidin- 4-yl]methyl]-2,3,3a,4,6,6a-hexahydrofuro[3,4-b]pyrrole-2- carboxamide

101 (2S,4R)-N-[[5-chloro-4-[6- (trifluoromethyl)-3-pyridyl)-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

102 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[15- fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide

103 (2R,3S)-3-fluoro-1-(4- fluorophenyl)salfonyl-N-[[3-methoxy-1-[6-(trifluoromethyl)- 3-pyridyl]pyrazol-4-yl]methyl]pyrrolidine-2- carboxamide

104 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[3- fluoro-4-(trifluoromethoxy)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

105 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-(methylamino)-6-[4- (trifluoromethyl)phenyl] pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

106 (2S,3R,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-3-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

107 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-4-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

108 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-methoxy-4-[6-(trifluoromethyl)- 3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

109 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-methoxy-4-[6-(trifluoromethyl)- 3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2- carboxamide

110 (2S,4R)-4-cyano-1-(4- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[4-(trifluoromethyl)phenyl]pyrazol- 4-yl]methyl]pyrrolidine-2- carboxamide

111 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin- 4-yl]methyl]pyrrolidine-2-carboxamide

112 (2S,4R)-N-[[3-cyano-5-[6- (trifluoromethyl)-3-pyridyl]phenyl]methyl]-4-fluoro- 1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

113 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[2- fluoro-4-(trifluoromethyl)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

114 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[3- fluoro-4-(trifluoromethyl)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

115 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3- pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

116 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-methoxy-5-[6-(trifluoromethyl)- 3- pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

117 (2S,4R)-N-[[3,5-difluoro-4-[6- (trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

118 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-methoxy-4-[6-(trifluoromethyl)- 3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

119 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-fluoro-6-[6-(trifluoromethyl)-3- pyridyl]-4-pyridyl]methyl]pyrrolidine-2- carboxamide

120 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-fluoro-4-[6-(trifluoromethyl)-3- pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

121 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[(5-fluoro-4-[3-(trifluoromethyl)-8- azabicyclo[3.2.1]octan-8-yl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

122 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]methyl]pyrrolidine-2- carboxamide

123 (1R,3S,5R)-2-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[3.1.0]hexane-3- carboxamide

124 (3R,6S)-2,2-difluoro-5-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]-5-azaspiro[2.4]heptane-6- carboxamide

125 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-methoxy-1-[6-(trifluoromethyl)- 3-pyridyl]pyrazol-4-yl]methyl]-2-methyl-pyrrolidine-2- carboxamide

126 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3- pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2- carboxamide

127 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-methoxy-6-[6-(trifluoromethyl)- 3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

128 (2S,4R)-N-[[4-(4,4-difluoro-1- piperidyl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

129 (2S,4R)-N-[[4-(6- azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

130 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-(trifluoromethyl)-4-[4- (trifluoromethyl)-1-piperidyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

131 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)-2-pyridyl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide

132 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[2-(trifluoromethyl)pyrimidin-5- yl]pyrazol-4- yl]methyl]pyrrolidine-2-carboxamide

133 (2S,4R)-N-[[6-[4- (difluoromethyl)-1-bicyclo[2.2.2]octanyl]pyrimidin- 4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl- pyrrolidine-2-carboxamide

134 (2S,4R)-4-fluoro-1-(3- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[4-(trifluoromethyl)phenyl]pyrazol- 4-yl]methyl]pyrrolidine-2- carboxamide

135 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[4-(trifluoromethyl)phenyl]pyrazol- 4-yl]methyl]pyrrolidine-2- carboxamide

136 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide

137 (2S,4R)-N-[[3-chloro-1-[4- (trifluoromethyl)phenyl]pyrazol-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

138 (2S.4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-2-methyl- N-[[6-[4-(tnfluoromethyl)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

139 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-fluoro-5-[6-(trifluoromethyl)-3- pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

140 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3- pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

141 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-2-[6-(trifluoromethyl)-3- pyridyl]-4-pyridyl]methyl]pyrrolidine-2- carboxamide

142 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-2-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

143 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethyl)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

144 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-fluoro-4-[4-(trifluoromethyl)-1- piperidyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

145 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethoxy)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

146 (2S,4R)-N-[[3-chloro-1-[6- (trifluoromethyl)-3-pyridyl]pyrazol-4-yl]methyl]-4- fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

147 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethylsulfanyl)phenyl] pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

148 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethyl)cyclohexen-1- yl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide

149 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethyl)cyclohexyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

150 (2S,4R)-1-(3,4- difluorophenyl)sulfonyl-4-fluoro- N-[[6-[4-(trifluoromethyl)phenyl] pyrimidin-4-yl]methyl] pyrrolidine-2-carboxamide

151 (2S,4R)-N-[[3-cyclopropyl-1-[6- (trifluoromethyl)-3-pyridyl]pyrazol-4-yl]methyl]-4- fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

152 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-methyl-6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

153 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3-methoxy-1-[6-(trifluoromethyl)- 3-pyridyl]pyrazol-4-yl]methyl]pyrrolidine-2- carboxamide

154 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide

155 (2S,4R)-N-[[6-(4- cyclopropylphenyl)pyrimidin-4-yl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

156 (2S,4R)-1-(3,4- difluorophenyl)sulfonyl-4-fluoro-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2- carboxamide

157 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]- 2-pyridyl]methyl]pyrrolidine-2-carboxamide

158 (2S,4R)-N-[[2-chloro-5-[2- (trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

159 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[4-(trifluoromethoxy)phenyl]-4- pyridyl]methyl]pyrrolidine-2- carboxamide

160 (2S,4R)-N-[[2-[4- (difluoromethoxy)phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

161 (2S,4R)-1-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-fluoro-5-[6-(trifluoromethyl)-3- pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

162 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-fluoro-5-[5-(trifluoromethyl)-2- pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

163 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[6-(trifluoromethyl)pyridazin-3- yl]phenyl]methyl]pyrrolidine-2-carboxamide

164 (2S,4R)-N-[[2-cyano-5-[2- (trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

165 (2S,4R)-N-[[2-chloro-6-[4- (difluoromethoxy)phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

166 (2R,3S)-N-[[5-cyano-2-[6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-3-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

167 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5- fluoro-4-[2-(trifluoromethyl)pyrimidin-5-yl]- 2-pyridyl]methyl]pyrrolidine-2-carboxamide

168 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

169 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5- methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

170 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-(2-methoxyethoxy)-4-[6- (trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2- carboxamide

171 (2S.4R)-1-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]- 3-pyridyl]methyl]pyrrolidine-2-carboxamide

172 (1R,4S,5S)-3-(4- fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]-3-azabicyclo[3.10]hexane-4- carboxamide

173 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)thiazol-4- yl]phenyl]methyl]pyrrolidine-2- carboxamide

174 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)thiazol-5- yl]phenyl]methyl]pyrrolidine-2- carboxamide

175 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[4-(trifluoromethyl)thiazol-2- yl]phenyl]methyl]pyrrolidine-2- carboxamide

176 (1S,2S,5R)-N-[[2-cyano-5-[2- (trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-(4- fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-2- carboxamide

177 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[4-(trifluoromethyl)phenyl]phenyl] methyl]pyrrolidine-2-carboxamide

178 (2S,4R)-N-[[2-[2-amino-6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

179 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2-[2-(methylamino)-6- (trifluoromethyl)-3-pyridyl)-4-pyridyl]methyl]pyrrolidine-2- carboxamide

180 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5- fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

181 (1R,5S)-4-(4- fluorophenyl)sulfonyl-N-[[3- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]-4-azabicyclo[3.1.0]hexane-5- carboxamide

182 (1R,5S)-4-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]-4-azabicyclo[3.1.0]hexane-5- carboxamide

183 (1S,2S,5R)-3-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide

184 (2S,4R)-N-[[5-chloro-2-[2- (trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

185 5-fluoro-2-(4- fluorophenyl)sulfonyl-N-[[5- fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]-2-azabicyclo[2.2.1]heptane-3- carboxamide

186 (2S,5S)-1-(4- fluorophenyl)sulfonyl-5-methyl- N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

187 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- fluoro-5-[2-(trifluoromethyl)pyrimidin-5- yl]phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide

188 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- methoxy-6-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

189 (2S,4R)-N-[[5-cyano-2-[2- (trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

190 (2S,4R)-4-fluoro-N-[[3-fluoro-5- [2-(2-methoxyethoxy)-6-(trifluoromethyl)-3- pyridyl]phenyl]methyl]-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

191 (2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6- methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]- 2-pyridyl]methyl]pyrrolidine-2-carboxamide

192 (2S,4R)-N-[[5-chloro-4-[2- (trifhioromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

193 (2S,4R,5S)-4-fluoro-1-(4- fluorophenyl)sulfonyl-5-methyl- N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

194 (2S)-1-(4-fluorophenyl)sulfonyl- 5,5-dimethyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide

195 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5-[2-(trifluoromethyl)pyrimidin-5-yl]- 3-pyridyl]methyl]pyrrolidine-2-carboxamide

196 (2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5- methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]- 4-pyridyl]methyl]pyrrolidine-2-carboxamide

197 (2S)-N-[[3-chloro-1-[4- (trifluoromethyl)phenyl]pyrazol-4-yl]methyl]-1-(4- fluorophenyl)sulfonyl-azetidine- 2-carboxamide

198 (2S)-1-(4-fluorophenyl)sulfonyl- 2-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]azetidine-2-carboxamide

199 (2S)-N-[[3-chloro-1-[6- (trifluoromethyl)-3-pyridyl]pyrazol-4-yl]methyl]-1- (4-fluorophenyl)sulfonyl-azetidine-2-carboxamide

200 (2S,4R)-1-(4- fluorophenyl)sulfonyl-4-methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4-yl]methyl]azetidine-2- carboxamide

201 (2S)-1-(4-fluorophenyl)sulfonyl- N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4- yl]methyl]azetidine-2- carboxamide

EE53. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE54. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE55. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE56. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE57. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof

EE58. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, C₆)haloalkyl, —S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE59. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R^(I-) isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE60. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE61. A compound of formula II:

wherein:

B is B², B³, or B⁵;

(1) the A group is:

B is B² and R⁵ is R^(5b);

(2) the A group is:

B is B³ and R⁵ is R^(5a);

(3) the A group is:

B is B⁵ and R⁵ is R^(5a);

B² is a pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with one ormore (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)-O- optionally substituted withone or more halogen;

R^(5b) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4,5, 6 or 7-membered heterocycle, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl or 4, 6, 7, or 8-membered heterocycleof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any 5-membered heterocycle ofR^(5b) is substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl and—S(C₁-C₆)haloalkyl; and

R⁶ is H or (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt thereof.

EE62. The compound of any one of embodiments EE53-EE61, wherein:

B² is pyridinyl, wherein any pyridinyl of B² is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-O(C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)haloalkyl, —CN, and 6-membered heteroaryl,wherein any 6-membered heteroaryl is optionally substituted with(C₁-C₆)alkyl or (C₁-C₆)haloalkyl;

B³ is a pyrimidinyl, wherein any pyrimidinyl of B³ is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, and NR⁶ ₂;

B⁵ is a phenyl optionally substituted with one or more groupsindependently selected from —CN, halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —O(C₁-C₆)alkyl, and —O(C₁-C₆)haloalkyl;

R^(5a) is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, orbicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl,cyclohexanyl, or bicyclo[2.2.2]octanyl of R^(5a) is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)-O- optionally substituted withone or more halogen;

R^(5b) is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl,pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl,wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl,pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-ylof R^(5b) is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl optionally substituted with one or more halogen,—O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, and NR⁶ ₂;

R¹ is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R¹ isoptionally substituted with one or more groups independently selectedfrom fluoro, chloro and —CN; and

R⁴ is H.

EE63. The compound of any one of embodiments EE53-EE62, wherein R^(5a)is

EE64. The compound of any one of embodiments EE53-EE62, wherein R^(5b)is

EE65. A compound of formula II:

wherein:

B is B³;

the A group is:

B is B³ and R⁵ is R^(5a);

B³ is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in thering or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring,wherein any 5-membered heteroaryl or 6-membered heteroaryl of B³ isoptionally substituted with one or more groups independently selectedfrom halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, andNR⁶ ₂, and wherein when B³ is pyrimidinyl which is attached to theremainder of formula II at the 4 and 6 positions of the pyrimidinyl,then R^(5a) is not pyrrolidinyl or substituted pyrrolidinyl;

R¹ is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, whereinany phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R¹ isoptionally substituted with one or more groups independently selectedfrom halogen, —CN, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

R⁴ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl; and

R^(5a) is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5,6 or 7-membered heterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl of R^(5a) is optionally substitutedwith one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)alkyl-O- optionally substitutedwith one or more halogen;

or a pharmaceutically acceptable salt thereof.

EE66. The compound of embodiment EE65, wherein:

B³ is a pyrimidinyl, wherein any pyrimidinyl of B³ is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —CN, and NR⁶ ₂; and

R⁵a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, orbicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl,cyclohexanyl, or bicyclo[2.2.2]octanyl of R^(5a) is optionallysubstituted with one or more groups independently selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo, and —O—(C₁-C₂)-Oalkyl- optionally substitutedwith one or more halogen.

EE67. The compound of embodiment EE66, wherein R^(5a) is

EE68. The compound of any one of embodiments EE1-EE30 wherein one R^(3e)group is halogen, —CN or (C₁-C₆)alkyl and the remaining R^(ae) groupsare independently selected from H, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl.

EE69. The compound of any one of embodiments EE1-EE30 wherein one R^(3e)group is halogen or (C₁-C₆)alkyl and the remaining R^(3e) groups areindependently selected from H and (C₁-C₆)alkyl.

In another embodiment of the invention, the compounds of Formula I or IIare isotopically-labeled by having one or more atoms therein replaced byan atom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of Formula I or IIare considered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of Formula I or IIinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and I^(125 I), respectively. These isotopically-labeled compoundswould be useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action onthe ion channels, or binding affinity to pharmacologically importantsite of action on the ion channels, particularly TRPAl. Certainisotopically-labeled compounds of Formula I or II, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection. Forexample, a compound of Formula I or II can be enriched with 1, 2, 5, 10,25, 50, 75, 90, 95, or 99 percent of a given isotope.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formula I or II can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

In another embodiment, the invention provides for a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to Formula I or II and a pharmaceutically acceptable carrier.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polyl)eptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyl)roline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional tyl)es of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistyl)e are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyk N-(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products tyl)ically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (tyl)icallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (includingstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of Formula I or II or and embodiment thereof and at least onepharmaceutically acceptable carrier. The compositions of the inventioncan be used to selectively inhibit TRPA1 in patients (e.g., humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions or medicaments comprising a compound of Formula I or II oran embodiment thereof, and its stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and a pharmaceutically acceptable carrier,diluent or excipient. In another embodiment, the invention provides forpreparing compositions (or medicaments) comprising compounds of theinvention. In another embodiment, the invention provides foradministering compounds of Formula I or II or its embodiments andcompositions comprising compounds of Formula I or II or an embodimentthereof to a patient (e.g., a human patient) in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit TRPA1 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the tyl)ical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of Formula I or II or anembodiment thereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A tyl)icalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament). Suitable carriers, diluents and excipients are wellknown to those skilled in the art and include buffers such as phosphate,citrate and other organic acids; antioxidants including ascorbic acidand methionine; preservatives (such as octadecyldimethylbenzyl ammoniumchloride; hexamethonium chloride; benzalkonium chloride, benzethoniumchloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methylor propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polyl)eptides; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine,or lysine; monosaccharides, disaccharides and other carbohydratesincluding glucose, mannose, or dextrins; chelating agents such as EDTA;sugars such as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). A active pharmaceutical ingredient of theinvention (e.g., a compound of Formula I or II or an embodiment thereof)can also be entrapped in microcapsules prepared, for example, bycoacervation techniques or by interfacial polymerization, for example,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington: The Science and Practice ofPharmacy: Remington the Science and Practice of Pharmacy (2005) 21^(st)Edition, Lippincott Williams & Wilkins, Philidelphia, Pa. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptablediluents, carriers, excipients and stabilizers are nontoxic torecipients at the dosages and concentrations employed, and include

Sustained-release preparations of a compound of the invention (e.g.,compound of Formula I or II or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I or II or an embodiment thereof, which matrices arein the form of shaped articles, e.g., films, or microcapsules. Examplesof sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. No. 4,485,045 and U.S. Pat. No. 4,544,545; andEP 102,324A). Ordinarily, the liposomes are of the small (about 200-800Angstroms) unilamelar tyl)e in which the lipid content is greater thanabout 30 mol % cholesterol, the selected proportion being adjusted forthe optimal therapy.

In one example, compounds of Formula I or II or an embodiment thereofmay be formulated by mixing at ambient temperature at the appropriatepH, and at the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of Formula I or II (or anembodiment thereof) is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of Formula I or II or an embodimentthereof are sterile. The compound may be stored, for example, as a solidor amorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of Formula Ior II or an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of Formula I or II or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

For topical formulations, it is desired to administer an effectiveamount of a pharmaceutical composition according to the invention totarget area, e.g., skin surfaces, mucous membranes, and the like, whichare adjacent to peripheral neurons which are to be treated. This amountwill generally range from about 0.0001 mg to about 1 g of a compound ofthe invention per application, depending upon the area to be treated,whether the use is diagnostic, prophylactic or therapeutic, the severityof the symptoms, and the nature of the topical vehicle employed. Apreferred topical preparation is an ointment, wherein about 0.001 toabout 50 mg of active ingredient is used per cc of ointment base. Thepharmaceutical composition can be formulated as transdermal compositionsor transdermal delivery devices (“patches”). Such compositions include,for example, a backing, active compound reservoir, a control membrane,liner and contact adhesive. Such transdermal patches may be used toprovide continuous pulsatile, or on demand delivery of the compounds ofthe present invention as desired.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of Formula I or II (or anembodiment thereof) to traverse the blood-brain barrier. Certainneurodegenerative diseases are associated with an increase inpermeability of the blood-brain barrier, such that a compound of FormulaI or II (or an embodiment thereof) can be readily introduced to thebrain. When the blood-brain barrier remains intact, several art-knownapproaches exist for transporting molecules across it, including, butnot limited to, physical methods, lipid-based methods, and receptor andchannel-based methods.

Physical methods of transporting a compound of Formula I or II (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood- brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel WafersTM, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhyl)ertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and U.S.Pat. No. 5,686,416).

Lipid-based methods of transporting a compound of Formula I or II (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of Formula I or II (or anembodiment thereof) in liposomes that are coupled to antibody bindingfragments that bind to receptors on the vascular endothelium of theblood- brain barrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of Formula I or II (or anembodiment thereof) in low-density lipoprotein particles (see, e.g.,U.S. Patent Application Publication No. 2004/0204354) or apolipoproteinE (see, e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of FormulaI or II (or an embodiment thereof) across the blood-brain barrierinclude, but are not limited to, using glucocorticoid blockers toincrease permeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of Formula I or II (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

Indications and Methods of Treatment

Representative compounds of the invention have been shown to modulateTRPA1 activity. Accordingly, the compounds of the invention are usefulfor treating diseases and conditions mediated by TRPA1 activity. Suchdiseases and conditions include but are not limited to: pain (acute,chronic, inflammatory, or neuropathic pain); itch or variousinflammatory disorders; inner ear disorders; fever or other disorders ofthermoregulation; tracheobronchial or diaphragmatic dysfunction;gastrointestinal or urinary tract disorders; chronic obstructivepulmonary disease; incontinence; and disorders associated with reducedblood flow to the CNS or CNS hyl)oxia.

In a specific embodiment, compounds of the invention can be administeredto treat pain, including but not limited to neuropathic and inflammatorypain, among others. Certain tyl)es of pain may be considered a diseaseor disorder, while other tyl)es may be considered symptoms of variousdiseases or disorders, and pain may include various etiologies.Exemplary tyl)es of pain treatable with a TRPA1-modulating agentaccording to the invention include pain associated with, arising from,or caused by: osteoarthritis, rotator cuff disorders, arthritis (e.g.,rheumatoid arthritis or inflammatory arthritis; see, Barton et al. Exp.Mol. Pathol. 2006, 81(2), 166-170), fibromyalgia, migraine and headache(e.g. cluster headache, sinus headache, or tension headache; see,Goadsby Curr. Pain Headache Reports 2004, 8, 393), sinusitis, oralmucositis, toothache, dental trauma, dental extractions, dentalinfections, burn (Bolcskei et al., Pain 2005, 117(3), 368-376), sunburn,dermatitis, psoriasis, eczema, insect sting or bite, musculoskeletaldisorders, bony fractures, ligamentous sprains, plantar fasciitis,costochondritis, tendonitis, bursitis, tennis elbow, pitcher's elbow,patellar tendonitis, repetitive strain injury, myofascial syndrome,muscle strain, myositis, temporomandibular joint disorder, amputation,low back pain, spinal cord injury, neck pain, whiplash, bladder spasms,G1 tract disorders, cystitis, interstitial cystitis, cholecystitis,urinary tract infection, urethral colic, renal colic, pharyngitis, coldsores, stomatitis, external otitis, otitis media (Chan et al., Lancet,2003, 361, 385), burning mouth syndrome, mucositis, esophageal pain,esophageal spasms, abdominal disorders, gastroesophageal reflux disease,pancreatitis, enteritis, irritable bowel disorder, inflammatory boweldisease, Crohn's disease, ulcerative colitis, colon distension,abdominal constriction,diverticulosis, diverticulitis, intestinal gas,hemorrhoids, anal fissures, anorectal disorders, prostatitis,epididymitis, testicular pain, proctitis, rectal pain, labor,childbirth, endometriosis, menstrual cramps, pelvic pain, vulvodynia,vaginitis, orolabial and genital infections (e.g. herpes simplex),pleurisy, pericarditis, non- cardiac chest pain, contusions, abrasions,skin incision (Honore, P. et al., J. Pharmacal Exp Ther., 2005, 314,410-21), postoperative pain, peripheral neuropathy, central neuropathy,diabetic neuropathy, acute herpetic neuralgia, post-herpetic neuralgia,trigeminal neuralgia, glossopharyngeal neuralgia, atyl)ical facial pain,gradiculopathy, HIV associated neuropathy, physical nerve damage,causalgia, reflex sympathetic dystrophy, sciatica, cervical, thoracic orlumbar radiculopathy, brachial plexopathy, lumbar plexopathy,neurodegenerative disorders, occipital neuralgia, intercostal neuralgia,supraorbital neuralgia, inguinal neuralgia, meralgia paresthetica,genitofemoral neuralgia, carpal tunnel syndrome, Morton's neuroma,post-mastectomy syndrome, post-thoracotomy syndrome, post-poliosyndrome, Guillain-Barre syndrome, Raynaud's syndrome, coronary arteryspasm (Printzmetal's or variant angina), visceral hyl)eralgesia(Pomonis, J. D. et al. J. Pharmacal. Exp. Ther. 2003, 306, 387; Walker,K. M. et al., Pharmacal. Exp. Ther. 2003, 304(1), 56-62), thalamic pain,cancer (e.g. pain caused by cancer, including osteolytic sarcoma, bytreatment of cancer by radiation or chemotherapy, or by nerve or bonelesions associated with cancer (see, Menendez, L. et al., Neurosci.Lett. 2005, 393 (1), 70-73; Asai, H. et al., Pain 2005, 117, 19-29), orbone destruction pain (see, Ghilardi, J. R. et al., J. Neurosci. 2005,25, 3126-31)), infection, or metabolic disease. Additionally, thecompounds may be used to treat pain indications such as visceral pain,ocular pain, thermal pain, dental pain, capsaicin-induced pain (as wellas other symptomatic conditions induced by capsaicin such as cough,lachrymation, and bronchospasm).

In another specific embodiment, compounds of the invention can beadministered to treat itch, which may arise from various sources, suchas dermatological or inflammatory disorders.

In another specific embodiment, compounds of the invention can beadministered to treat inflammatory disorders, including disordersselected from the group consisting of: renal or hepatobiliary disorders,immunological disorders, medication reactions and unknown/idiopathicconditions. Inflammatory disorders treatable with an inventive agentinclude, for example, inflammatory bowel disease (1BO), Crohn's disease,and ulcerative colitis (Geppetti, P. et al., Br. J. Pharmacal. 2004,141, 1313-20; Yiangou, Y. et al., Lancet 2001, 357, 1338-39; Kimball, E.S. etal., Neurogastroenterol. Motif., 2004,16, 811), osteoarthritis(Szabo, A. et al., J. Pharmacal. Exp. Ther. 2005, 314, 111-119),psoriasis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis,multiple sclerosis, scleroderma, glomerulonephritis, pancreatitis,inflammatory hepatitis, asthma, chronic obstructive pulmonary disease,allergic rhinitis, uveitis, and cardiovascular manifestations ofinflammation including atherosclerosis, myocarditis, pericarditis, andvasculitis.

In another specific embodiment, compounds of the invention can beadministered to treat inner ear disorders. Such disorders include, forexample, hyl)eracusis, tinnitus, vestibular hyl)ersensitivity, andepisodic vertigo.

For example, compounds of the invention can be administered to treattracheobronchial and diaphragmatic dysfunctions including, for example,asthma and allergy-related immune responses (Agopyan, N. et al., Am. J.Physiol. Lung Cell Mol. Physiol. 2004, 286, L563-72; Agopyan, N. et al.,Toxicol. Appl. Pharmacal. 2003, 192, 21-35), cough (e.g., acute orchronic cough, or cough caused by irritation from gastroesophagealreflux disease; see, Lalloo, U. G. et al., J. Appl. Physiol. 1995,79(4), 1082-7), bronchospasm, chronic obstructive pulmonary disease,chronic bronchitis, emphysema, and hiccups (hiccoughs, singultus).

In another specific embodiment, compounds of the invention can beadministered to treat gastrointestinal and urinary tract disorders suchas, bladder overactivity, inflammatory hyl)eralgesia, visceralhyl)erreflexia of the urinary bladder, hemorrhagic cystitis (Dinis, P.et al., J. Neurosci., 2004, 24, 11253-11263), interstitial cystitis(Sculptoreanu, A. et al., Neurosci Lett., 2005, 381, 42-46),inflammatory prostate disease, prostatitis (Sanchez, M. et al., Eur JPharmacal., 2005, 515, 20-27), nausea, vomiting, intestinal cramping,intestinal bloating, bladder spasms, urinary urgency, defecation urgencyand urge incontinence.

In another specific embodiment, compounds of the invention can beadministered to treat disorders associated with reduced blood flow tothe CNS or CNS hyl)oxia. Such disorders include, for example, headtrauma, spinal injury, thromboembolic or hemorrhagic stroke, transientischaemic attacks, cerebral vasospasm, hyl)oglycaemia, cardiac arrest,status epilepticus, perinatal asphyxia, Alzheimer's disease, andHuntington's Disease.

In other embodiments, compounds of the invention can be administered totreat other diseases, disorders, or conditions mediated through TRPA1activity, such as: anxiety; learning or memory disorders; eye-relateddisorders (such as glaucoma, vision loss, increased intraocularpressure, and conjunctivitis); baldness (e.g., by stimulating hairgrowth); diabetes (including insulin-resistant diabetes or diabeticconditions mediated by insulin sensitivity or secretion); obesity (e.g.,through appetite suppression); dyspepsia; biliary colic; renal colic;painful bladder syndrome; inflamed esophagus; upper airway disease;urinary incontinence; acute cystitis; and envenomations (such as marine,snake, or insect stings or bites, including jellyfish, spider, orstingray envenomations).

In one specific embodiment, compounds of the invention are administeredto treat pain (including but not limited to acute, chronic, neuropathicand inflammatory pain), arthritis, itch, cough, asthma, or inflammatorybowel disease.

In another embodiment, the invention provides for a method for treatingneuropathic pain or inflammatory pain, comprising the step ofadministering a therapeutically effective amount of a compound accordingto Formula I or II (e.g., a compound as described in any one of E1-E50,E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, orEE1-EE67 above) to a subject in need thereof

In another embodiment, the invention provides for a compound of FormulaI or II (e.g., a compound as described in any one of E1-E50, E1A-E33A,E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67above) or a pharmaceutically acceptable salt thereof for modulatingTRPA1 activity.

In another embodiment, the invention provides for a compound of FormulaI or II (e.g., a compound as described in any one of E1-E50, E1A-E33A,E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67above), or a pharmaceutically acceptable salt thereof for use in medicaltherapy.

In another embodiment, the invention provides for a method for treatinga respiratory disorder selected from chronic obstructive pulmonarydisorder (COPD), asthma, allergic rhinitis and bronchospasm, comprisingthe step of administering a therapeutically effective amount of acompound according to Formula I or II (e.g., a compound as described inany one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E,Table 1, Table 2, or EE1-EE67 above) to a subject in need thereof.

In another embodiment, the invention provides for a compound of FormulaI or II (e.g., a compound as described in any one of E1-E50, E1A-E33A,E1B-E24B, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or apharmaceutically acceptable salt thereof for the treatment orprophylaxis of a respiratory disorder.

In another embodiment, the invention provides for the use of a compoundof Formula I or II (e.g., a compound as described in any one of E1-E50,E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, orEE1-EE67 above) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment or prophylaxis of arespiratory disorder.

In another embodiment, the invention provides for a method for treatinga respiratory disorder in a mammal (e.g., a human) comprisingadministering a compound of Formula I or II (e.g., a compound asdescribed in any one of E1-E50, E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D,E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or a pharmaceuticallyacceptable salt thereof to the mammal.

In another embodiment, the invention provides for a method formodulating TRPA1 activity, comprising contacting TRPA1 with a compoundof Formula I or II (e.g., a compound as described in any one of E1-E50,E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, orEE1-EE67 above) or a salt thereof.

In another embodiment, the invention provides for a compound of FormulaI or II (e.g., a compound as described in any one of E1-E50, E1A-E33A,E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67above) or a pharmaceutically acceptable salt thereof for the treatmentor prophylaxis of a disease or condition mediated by TRPA1 activity.Within aspects of this embodiment, the disease or condition is pain(including but not limited to acute, chronic, neuropathic andinflammatory pain), itch, an inflammatory disorder, an inner eardisorder, fever or another disorder of thermoregulation,tracheobronchial or diaphragmatic dysfunction, a gastrointestinal orurinary tract disorder, chronic obstructive pulmonary disease,incontinence, or a disorder associated with reduced blood flow to theCNS or CNS hyl)oxia. Within certain aspects of this embodiment, whereinthe disease or condition is pain (including but not limited to acute,chronic, neuropathic and inflammatory pain), arthritis, itch, cough,asthma, inflammatory bowel disease, or an inner ear disorder.

In another embodiment, the invention provides for the use of a compoundof Formula I or II (e.g., a compound as described in any one of E1-E50,E1A-E33A, E1B-E24B, E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, orEE1-EE67 above) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment or prophylaxis of adisease or condition that is mediated by TRPA1 activity. Within aspectsof this embodiment, the disease or condition is pain (including but notlimited to acute, chronic, neuropathic and inflammatory pain), itch, aninflammatory disorder, an inner ear disorder, fever or another disorderof thermoregulation, tracheobronchial or diaphragmatic dysfunction, agastrointestinal or urinary tract disorder, chronic obstructivepulmonary disease, incontinence, or a disorder associated with reducedblood flow to the CNS or CNS hyl)oxia. Within aspects of thisembodiment, the disease or condition is pain (including but not limitedto acute, chronic, neuropathic and inflammatory pain), arthritis, itch,cough, asthma, inflammatory bowel disease, or an inner ear disorder.

In another embodiment, the invention provides for a method for treatinga disease or condition mediated by TRPA1 activity in a mammal (e.g., ahuman), comprising administering a compound of Formula I or II (e.g., acompound as described in any one of E1-E50, E1A-E33A, E1B-E24B,E1C-E29C, E1D-E26D, E1E-E33E, Table 1, Table 2, or EE1-EE67 above) or apharmaceutically acceptable salt thereof to the mammal. Within certainaspects of this embodiment, the disease or condition is pain (includingbut not limited to acute, chronic, neuropathic and inflammatory pain),itch, an inflammatory disorder, an inner ear disorder, fever or anotherdisorder of thermoregulation, tracheobronchial or diaphragmaticdysfunction, a gastrointestinal or urinary tract disorder, chronicobstructive pulmonary disease, incontinence, or a disorder associatedwith reduced blood flow to the CNS or CNS hyl)oxia. Within certainaspects of this embodiment, the disease or condition is pain (includingbut not limited to acute, chronic, neuropathic and inflammatory pain),arthritis, itch, cough, asthma, inflammatory bowel disease, or an innerear disorder.

In one aspect, compounds of the invention demonstrate surprisinglysuperior stability in in vivo rat pharmacokinetic (PK) studies overrelated compounds. Monofluorination, specifically at the 4-position ofthe proline ring, enhances the stability of the compounds, such that thecompounds do not clear as rapidly from the blood as other relatedcompounds. For example, a monofluorinated compound at the proline3-position,(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide,possess the highest stability (slowest clearance) over relateddifluorinated, non-fluorinated, and 3-fluorinated compounds as shownbelow:

Rat PK Clp Structure Name (ml/min/kg)

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide  15

(2S)-1-(4- fluorophenyl)sulfonyl-N-[[6- [6-(trifluoromethyl)-3-pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2- carboxamide  98

(2S)-4,4-difluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide  30

(2R,3S)-3-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide 101

Other representative compounds, commensurate in scope of the presentinvention, demonstrate similar surprisingly enhanced PK stability as(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide,shown below:

Rat PK Clp Structure Name (ml/min/kg)

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[5- fluoro-4-[2-(trifluoromethyl)pyrimidin-5- yl]-2- pyridyl]methyl]pyrrolidine-2-carboxamide  5.9

(2S,4R)-4-cyano-1-(4- fluorophenyl)sulfonyl-N-[[6- [4-(trifluoromethyl)phenyl] pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide  7.6

(2S,4R)-N-[[2,6-bis[6- (trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1- (4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide  9.1

(2S,4R)-N-[[3-[5- (difluoromethyl)pyrazin-2-yl]-5-fluoro-phenyl]methyl]- 4-fluoro-1-(4- fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide  9.9

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-4- methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide 11.3

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[3- methoxy-1-[6-(trifluoromethyl)-3- pyridyl]pyrazol-4- yl]methyl]pyrrolidine-2-carboxamide 13  

(2S,4R)-N-[[6-[4- (difluoromethoxy)phenyl]pyrimidin-4-yl]methyl]-4-fluoro- 1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide 13.2

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-2- methyl-N-[[6-[6-(trifluoromethyl)-3- pyridyl]pyrirnidin-4- yl]methyl]pyrrolidine-2-carboxamide 15  

(2S,4R)-4-fluoro-1-(4- fluorophenyl)sulfonyl-N-[[2- methoxy-6-[6-(trifluoromethyl)-3- pyridyl]pyrimidin-4- yl]methyl]pyrrolidine-2-carboxamide 16.5

Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of ion channel-mediateddiseases and conditions. For example, a compound of the invention may beadministered simultaneously, sequentially or separately in combinationwith other therapeutic agents, including, but not limited to:

-   opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,    levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,    propoxyl)hene, nalmefene, fentanyl, hydrocodone, hydromorphone,    meripidine, methadone, nalorphine, naloxone, naltrexone,    buprenorphine, butorphanol, nalbuphine and pentazocine;-   non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g.,    aspirin);-   nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen,    naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal,    etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen,    indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic    acid, meloxicam, nabumetone, naproxen, nimesulide,    nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam,    sulfasalazine, sulindac, tolmetin and zomepirac;-   anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine,    valproate, topiramate, gabapentin and pregabalin;-   antidepressants such as tricyclic antidepressants, e.g.,    amitriptyline, clomipramine, despramine, imipramine and    nortriptyline;-   COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib,    valdecoxib, deracoxib, etoricoxib, and lumiracoxib;-   alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine,    guanfacine, dexmetatomidine, modafinil, and    4-amino-6,7-dimethoxy-2-(5- methane    sulfonamido-1,2,3,4-tetrahydroisoquino1-2-yl)-5-(2-pyridyl)    quinazoline;-   barbiturate sedatives, e.g., amobarbital, aprobarbital,    butabarbital, butabital, mephobarbital, metharbital, methohexital,    pentobarbital, phenobartital, secobarbital, talbutal, theamylal and    thiopental;-   tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1    antagonist, e.g., (□R,    9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione    (TAK-637),    5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one    (MK-869), aprepitant, lanepitant, dapitant or    3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine    (2S,3S);-   coal-tar analgesics, in particular paracetamol;-   serotonin reuptake inhibitors, e.g., paroxetine, sertraline,    norfluoxetine (fluoxetine desmethyl metabolite), metabolite    demethylsertraline, ′3 fluvoxamine, paroxetine, citalopram,    citalopram metabolite desmethylcitalopram, escitalopram,    d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine,    dapoxetine, nefazodone, cericlamine, trazodone and fluoxetine;-   noradrenaline (norepinephrine) reuptake inhibitors, e.g.,    maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,    tomoxetine, mianserin, buproprion, buproprion metabolite    hydroxybuproprion, nomifensine and viloxazine (Vivalan®)),    especially a selective noradrenaline reuptake inhibitor such as    reboxetine, in particular (S,S)-reboxetine, and venlafaxine    duloxetine neuroleptics sedative/anxiolytics;-   dual serotonin-noradrenaline reuptake inhibitors, such as    venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,    clomipramine, clomipramine metabolite desmethylclomipramine,    duloxetine, milnacipran and imipramine;-   acetylcholinesterase inhibitors such as donepezil;-   5-HT3 antagonists such as ondansetron;-   metabotropic glutamate receptor (mGluR) antagonists;-   local anaesthetic such as mexiletine and lidocaine;-   corticosteroid such as dexamethasone;-   antiarrhythimics, e.g., mexiletine and phenytoin;-   muscarinic antagonists, e.g.,, tolterodine, propiverine, tropsium t    chloride, darifenacin, solifenacin, temiverine and ipratropium;-   cannabinoids;-   vanilloid receptor agonists (e.g., resinferatoxin) or antagonists    (e.g., capsazepine);-   sedatives, e.g., glutethimide, meprobamate, methaqualone, and    dichloralphenazone;-   anxiolytics such as benzodiazepines,-   antidepressants such as mirtazapine,-   topical agents (e.g., lidocaine, capsacin and resiniferotoxin);-   muscle relaxants such as benzodiazepines, baclofen, carisoprodol,    chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;-   anti-histamines or H1 antagonists;-   NMDA receptor antagonists;-   5-HT receptor agonists/antagonists;-   PDEV inhibitors;-   Tramadol®;-   cholinergic (nicotinc) analgesics;-   alpha-2-delta ligands;-   prostaglandin E2 subtyl)e antagonists;-   leukotriene B4 antagonists;-   5-lipoxygenase inhibitors; and-   5-HT3 antagonists.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

In another embodiment, provided is an invention as hereinbeforedescribed.

General Preparation of Compounds of Formula I or II

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: N.Y., 1991,Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier SciencePublishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions,Wiley & Sons: N.Y., 1991, Volumes 1-40.

The following synthetic reaction schemes are merely illustrative of somemethods by which the compounds of the present invention can besynthesized, and various modifications to these synthetic reactionschemes can be made and will be suggested to one skilled in the arthaving referred to the disclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Compounds of the invention can be made according methods known in art.In one aspect, compounds of the invention can be made as outlined inSchemes 1-4 herein. In Schemes 1-4, the variable A, B, R¹, R⁴, R^(Z1)and R⁵ have the meaning as defined for Formula I or II. R is annon-interfering group and Hal represents halogen.

According to Scheme 1, an N-PG-substituted carboxylic acid, where theamine may be protected using well known protecting groups (PG) asdescribed in “Protective Groups in Organic Synthesis” [T. W. Greene andP. G. M. Wuts, 3^(rd) Edition, John Wiley and Sons, N.Y. 1999], may bereacted with an amine of formula 2 to yield an amide of formula 3. Thistransformation is well-documented in the chemical literature andfamiliar to those skilled in the art. It proceeds under variousreactions conditions, for example, the carboxylic acid and amine can becombined in an aprotic solvent such as N,N-dimethylformamide and treatedwith any number of peptide coupling reagents such as2-(1H-7-azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium or bromo-tris-pyrrolidinophosphoniumhexafluorophosphate.. A large variety and number ofN-PG-substituted carboxylic acids may be purchased from commercialsources. Examples include(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,1-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid, and(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid.The amine coupling partner of formula 2 in Scheme 1 can be purchased ormade from the methods described in Scheme 3. An intermediate of formula4 can then be made by a variety of well-established methods. Forexample, an intermediate of formula 3 can be treated with hydrochloricacid, trifluoroacetic acid, or other reagent to provide an intermediateof formula 4. An intermediate of formula 4 can then be coupled with aR¹-substituted sulfonyl chloride by a variety of well-establishedmethods to yield compounds of formula 1. For example, the sulfonylchloride and amine can be combined in an aprotic solvent such asdichloromethane and treated with an excess of base such as triethylamineor potassium carbonate. Numerous sulfonyl chlorides can be obtained fromcommercial sources including benzenesulfonyl chloride,4-fluorobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride,pyridine-3-sulfonyl chloride, 2-chloropyridine-5-sulfonyl chloride ,3-cyanobenzenesulfonyl chloride and 2-thiazolesulfonyl chloride.

Alternatively, compounds of the invention may be made according to theprocesses outlined in Scheme 2. According to Scheme 2, sulfonamides offormula 5 can be readily prepared according to well established methodsby combining sulfonyl chlorides containing le with amino acids. Forexample, sulfonyl chloride may be added to a solution of the amino acidand an organic base such as triethylamine in a polar, aprotic solventsuch as THF. Alternatively, the reagents may be combined in a moderatelybasic solvent such as pyridine. A large variety and number of aminoacids may be purchased from commercial sources. An intermediate offormula 5 may then be reacted with an amine of formula 2. Thistransformation is well-documented in the chemical literature andfamiliar to those skilled in the art. It proceeds under variousreactions conditions, for example, the carboxylic acid and amine can becombined in an aprotic solvent such as N,N-dimethylformamide and treatedwith any number of peptide coupling reagents such as2-(1H-7-azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium or bromo-tris-pyrrolidinophosphoniumhexafluorophosphate.

As shown in Scheme 3, intermediates of the general structure 2 may besynthesized by well-established methods. For example, the bond betweenthe central aromatic ring and R⁵ may be created by a number of efficientmetal-catalyzed coupling methods such as method that has come to beknown as the Suzuki coupling. Under this scheme either of the two groupsto be linked may be boronic acid or ester or halogen/pseudo-halogen. Theother coupling partner would then be halogen/pseudo-halogen or boronicacid/ester respectively. Conditions for effecting this coupling includeheating the boronic acid and aryl halide in a polar solvent mixture suchas dioxane/water in the presence of an organic or inorganic base such astriethylamine or potassium carbonate and using a palladium catalyst suchas tetrakis [triphenylphosphine] palladium or palladium (II) acetate.

Numerous starting materials of formula 2a and 2b may be purchasedcommercially. For example,2-chloro-6-(trifluoromethoxy)-4-pyridinemethanamine,2-bromo-4-pyridinemethanamine hydrochloride,(3,6-dichloropyridazin-4-yl)methanamine,4-aminomethyl-6-chloropyrimidine, (3-aminomethylphenyl)boronic acidhydrochloride, 5-(aminomethyl)-2-fluorophenylboronic acid, HCl,[5-(aminomethyl)-2-methylphenyl]boronic acid,(5-bromopyridin-3-yl)methanamine, 3-(aminomethyl)-5-bromopyridin-2-ol,(5-bromo-2-chloro-pyridin-3-yl)-methanamine hydrochloride,(4-bromopyridin-2-yl)methanamine,(4-bromo-6-(trifluoromethyl)pyridin-2-yl)methanamine,2-bromo-4-pyridinethylamine, (2-bromo-5-chloropyridin-4-yl)methanamine.

As shown in Scheme 4, compounds of the invention in which B ispyrimidinyl may be made by known methods for synthesizing pyrimidines.For example, they may be made by a process outlined in Scheme 4 in whichan arylketoester is reacted with an amidine or an appropriate equivalentto give 4-arylpyrimidinones, wherein R^(Z1) and R⁵ have values describedherein for compounds of formula I and II. This intermediate could thenby chlorinated under established conditions such as heating inphosphorus oxychloride. The chloride could then be converted to thenitrile by a number of well-known methods and then reduced to theaminomethyl group. For example, the chloropyrimidine could be heatedwith potassium cyanide in a polar solvent such as DMSO to yieldcyanopyrimidine. Alternatively, the chloropyrimidine could be treatedwith zinc cyanide and a catalytic amount of a transition metal catalystsuch as tetrakis[triphenylphosphine]palladium in a polar solvent such asN-methylpyrrolidinone or THF. The nitrile could be subsequently reducedby dissolving it in a polar solvent such as ethanol and treated with acatalytic amount of metal catalyst such as palladium on carbon andshaken under a hydrogen atmosphere or pressure, for example, 60 psi.

EXAMPLES

Although certain exemplary embodiments are depicted and describedherein, the compounds of the present invention can be prepared usingappropriate starting materials according to the methods describedgenerally herein and/or by methods available to one of ordinary skill inthe art.

Intermediates and final compounds were purified by either flashchromatography, and/or by reverse-phase preparative HPLC (highperformance liquid chromatography), and/or by supercritical fluidchromatography. Unless otherwise noted, flash chromatography was carriedout using pre-packed silica gel cartridges from either ISCO or SiliCycleon an ISCO CombiFlash® chromatography instrument (from Teledyne Isco,Inc.). Reverse-phase preparative HPLC was performed using a (1) PolarisC-18 5 μM column (50×21 mm), or (2) XBridge Prep C-18 OBD 5 μM column(19×150 mm). Supercritical fluid chromatography was carried out usingpacked columns by Chiral Technologies, Chiralpak AD, Chiralpak AS,Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel OD, or Chiralcel OJwith column dimensions such as (1) 4.6 cm×5 cm, 3 μM, (2) 4.6 cm×5 cm, 5μM, or (3) 15 cm×21.2 mm, 5 μM.

Mass spectrometry (MS) was performed using a (1) Sciex 15 massspectrometer in ES+mode, or (2) Shimadzu LCMS 2020 mass spectrometer inESI+mode. Mass spectra data generally only indicates the parent ionsunless otherwise stated. MS or HRMS data is provided for a particularintermediate or compound where indicated.

Nuclear magnetic resonance spectroscopy (NMR) was performed using a (1)Bruker AV III 300 NMR spectrometer, (2) Bruker AV III 400 NMRspectrometer, or (3) Bruker AV III 500 NMR spectrometer, and referencedto tetramethylsilane. NMR data is provided for a particular intermediateor compound where indicated.

All reactions involving air-sensitive reagents were performed under aninert atmosphere. Reagents were used as received from commercialsuppliers unless otherwise noted.

Example 1 Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamideStep1: Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methylpyrrolidine-2-carboxylic acid.

A mixture of (S)-2-methylpyrrolidine-2-carboxylic acid (0.1 g, 0.77mmol), 4-fluorobenzene-1-sulfonyl chloride (0.16 g, 0.81 mmol) and 10 NNaOH (1.5 mL, 15 mmol) in THF (1.5 mL) was stirred at room temperaturefor 12 h. The mixture was diluted with EtOAc, acidified with 3 N HCl (pH2-3) and separated. The aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were washed with brine (2×), dried (Na₂SO₄),filtered, and concentrated to provide crude(S)-1-(4-fluorophenylsulfonyl)-2-methylpyrrolidine-2-carboxylic acid asa white solid, which was used in the next step without any furtherpurification.

Step 2: Preparationof(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of crude(S)-1-(4-fluorophenylsulfonyl)-2-methylpyrrolidine-2-carboxylic acid(0.043 g, 0.15 mmol),(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine (0.046mg, 0.18 mmol), EDC (0.057 mg, 0.3 mmol), HOAt (0.042 mg, 0.3 mmol) andEt₃N (0.063 mL, 0.45 mmol) in DMF (1.5 mL) was stirred at roomtemperature for 48 h. The mixture was diluted with water and extractedwith EtOAc (2×). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated. The resulting residue was purified byreverse phase HPLC affording the title compound (37 mg, 9%, two steps):¹H-NMR (400 MHz, DMSO-d₆) δ 9.47 (d, J=1.9 Hz, 1H), 9.29 (d, J=1.2 Hz,1H), 8.78 (dd, J=8.2, 1.7 Hz, 1H), 8.62 (t, J=5.8 Hz, 1H), 8.25 (d,J=0.9 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.02-7.93 (m, 2H), 7.48-7.39 (m,2H), 4.61 (dd, J=17.4, 6.3 Hz, 1H), 4.41 (dd, J=17.4, 5.4 Hz, 1H),3.67-3.58 (m, 1H), 3.38-3.31 (m, 1H), 2.22-2.13 (m, 1H), 2.06-1.95 (m,1H), 1.94-1.80 (m, 2H), 1.50 (s, 3H).

Example 2 Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamide.

(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamideStep1: Preparation of tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate.

A mixture of 1-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid(0.1 g, 0.51 mmol),(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine (0.13 mg,0.51 mmol), iPr₂NEt (0.17 mL, 0.98 mmol), PyAOP (0.29 mg, 0.54 mmol) and4-DMAP (0.006 mg, 0.05 mmol) in DMF (3 mL) was stirred at roomtemperature for 3 h. The mixture was washed with saturated aqueousNaHCO₃ solution and brine, and extracted with EtOAc (2×). The combinedorganic layers were dried (Na₂SO₄) filtered, passed through a silica gelplug washing with EtOAc, and concentrated to provide crude tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate,which was used in the next step without any further purification.

Step 2: Preparation of2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride.

To a solution of crude tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate(0.22 g, 0.49 mmol), in CH₂Cl₂ (2 mL) was added 4 N HCl in dioxane (1mL, 4 mmol) and the mixture stirred at room temperature for 3 h. Themixture was concentrated under reduced pressure to provide2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride as a crude salt, which was used in the next step without anyfurther purification.

Step 3: Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamide.

A mixture of crude2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride (0.085 g, 0.22 mmol), 4-fluorobenzene-1-sulfonyl chloride(0.047 mg, 0.24 mmol), and Et₃N (0.15 mL, 1.1 mmol) in CH₂Cl₂ (2 mL) wasstirred at room temperature for 12 h. The mixture was diluted with waterand extracted with CH₂Cl₂ (2×). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated. The resulting residue was purifiedby chiral SFC affording the title compound (22 mg) as the slower elutingisomer: ¹H-NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J=1.9 Hz, 1H), 9.32 (d,J=1.2 Hz, 1H), 8.79 (dd, J=8.2, 1.7 Hz, 1H), 8.74 (t, J=5.9 Hz, 1H),8.18 (d, J=0.9 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 8.03-7.95 (m, 2H),7.54-7.43 (m, 2H), 4.66 (dd, J=17.4, 6.4 Hz, 1H), 4.49 (dd, J=17.4, 5.4Hz, 1H), 3.97-3.86 (m, 1H), 3.82-3.74 (m, 1H), 2.10-1.98 (m, 1H), 1.54(s, 3H).

Example 3 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamideStep 1: Preparation of (2S,4R)-tert-butyl4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidine-1-carboxylate.

(2S,4R)-tert-butyl4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidine-1-carboxylatewas prepared by the procedure described in Example 2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid.

Step 2: Preparation of(2S,4R)-4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidiniumchloride.

(2S,4R)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamidewas prepared by the procedure described in Example 2, step 2.

Step 3: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedure described in Example 2,step 3 (29 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J=1.9 Hz, 1H), 9.30(d, J=1.2 Hz, 1H), 9.11 (t, J=5.9 Hz, 1H), 8.79 (dd, J=8.3, 1.7 Hz, 1H),8.23 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.05-7.98 (m, 2H), 7.47 (t, J=8.8Hz, 2H), 5.21 (d, J=52.4 Hz, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.25 (dd,J=9.8, 7.2 Hz, 1H), 3.79-3.60 (m, 2H), 2.46-2.37 (m, 1H), 2.25-2.04 (m,1H).

Example 4 Preparation of(2S,4S)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

(2S,4S)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,and Example 2, steps 2 and 3 (37 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ 9.43(d, J=1.9 Hz, 1H), 9.28 (d, J=1.2 Hz, 1H), 8.89 (t, J=6.1 Hz, 1H), 8.75(dd, J=8.1, 1.8 Hz, 1H), 8.14-8.01 (m, 4H), 7.55-7.43 (m, 2H), 5.26 (dt,J=53.3, 3.7 Hz, 1H), 4.61-4.44 (m, 2H), 4.39 (d, J=9.5 Hz, 1H), 3.81(dd, J=22.4, 12.2 Hz, 1H), 3.45 (ddd, J=36.0, 12.3, 3.8 Hz, 1H),2.37-2.24 (m, 1H), 2.07-1.85 (m, 1H).

Example 5 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, andExample 2, steps 2 and 3 (107 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ 9.25 (s,1H), 9.11 (t, J=5.7 Hz, 1H), 8.40 (d, J=8.1 Hz, 2H), 8.15 (s, 1H),8.07-7.99 (m, 2H), 7.88 (d, J=8.1 Hz, 2H), 7.47 (t, J=8.6 Hz, 2H), 5.21(d, J=52.4 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.31-4.22 (m, 1H), 3.78-3.59(m, 2H), 2.48-2.38 (m, 1H), 2.23-2.05 (m, 1H).

Example 6 Preparation of(2S,4R)-4-fluoro-1-(3-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

(2S,4R)-4-fluoro-1-(3-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, Example 2,step 2 and Example 2, step 3 using 3-fluorobenzene-1-sulfonyl chloride(108 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ 9.25 (d, J=1.1 Hz, 1H), 9.13 (t,J=5.8 Hz, 1H), 8.40 (d, J=8.1 Hz, 2H), 8.15 (s, 1H), 7.88 (d, J=8.3 Hz,2H), 7.85-7.77 (m, 2H), 7.73-7.65 (m, 1H), 7.63-7.56 (m, 1H), 5.22 (d,J=52.3 Hz, 1H), 4.59-4.45 (m, 2H), 4.31 (dd, J=9.9, 7.1 Hz, 1H),3.83-3.58 (m, 2H), 2.48-2.39 (m, 1H), 2.23-2.05 (m, 1H).

Example 7 Preparation of(R)-1-(4-fluorophenylsulfonyl)-2-(hydroxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step1:_(—) Preparation of(3R,7aS)-3-(trichloromethyl)-tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.

A solution of (2S)-pyrrolidine-2-carboxylic acid (5.8 g, 50.38 mmol),2,2,2-trichloroacetaldehyde (12.4 g, 84.13 mmol) in chloroform (100 mL)was stirred for 18 h at 75° C. in an oil bath. The resulting mixture waswashed with water (2×) and brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was recrystallized from ethanol toafford the title compound (6.2 g, 50%) as a white solid.

Step 2: Preparation of(3R,7aR)-7a-(benzyloxymethyl)-3-(trichloromethyl)-tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.

n-BuLi (36 mL, 90 mmol) was added dropwise to a solution ofdiisopropylamine (9.1 g, 89.93 mmol,) in THF (60 mL) with stirring at−78° C. under nitrogen and the reaction mixture was stirred for another15 min at 0° C. The resulting solution was added dropwise into asolution of(3R,7aS)-3-(trichloromethyl)-hexahydropyrrolo[1,2-c][1,3]oxazol-1-one(14.6 g, 59.71 mmol) in THF (100 mL) within 30 min at −78° C. andstirred for another 30 min at −78° C. Then[(chloromethoxy)methyl]benzene (14.1 g, 90.03 mmol) was added dropwise.The resulting solution was stirred for an additional 2 h at −40° C. andquenched by the addition of water (150 mL), extracted with EtOAc (3×200mL) and separated. The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:10)to afford the title compound (10 g, 38%) as light yellow oil.

Step 3: Preparation of (R)-methyl2-(benzyloxymethyl)pyrrolidine-2-carboxylate.

Sodium methoxide (890 mg, 16.47 mmol) was added portionwise to asolution of(3R,7aR)-7a-[(benzyloxy)methyl]-3-(trichloromethyl)-hexahydropyrrolo[1,2-c][1,3]oxazol-1-one(10 g, 27.42 mmol) in methanol (100 mL). The resulting solution wasstirred for 30 min at room temperature and acetyl chloride (38 mL,532.50 mmol) was added dropwise with stirring over 1 h at 0° C. Theresulting solution was allowed to react for an additional 24 h at roomtemperature and concentrated under reduced pressure. The residue wasdiluted with EtOAc (50 mL) and saturated aqueous sodium carbonate (100mL), extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine (100 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to afford the title compound (5.85 g, 86%) aslight red oil.

Step 4: Preparation of (R)-methyl2-(benzyloxymethyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxylate.

4-Fluorobenzene-1-sulfonyl chloride (6.8 g, 34.94 mmol) was addeddropwise to a solution of methyl(2R)-2-[(benzyloxy)methyl]pyrrolidine-2-carboxylate (5.8 g, 23.26 mmol),DIPEA (9 g, 69.64 mmol), 4-dimethylaminopyridine (280 mg, 2.29 mmol) inCH₂Cl₂ (150 mL) with stirring at 0° C. The resulting solution wasstirred for 18 h at room temperature and diluted with CH₂Cl₂ (150 mL),washed with 2 N HCl (2×) and brine. The mixture was dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford the titlecompound (8.3 g, 88%) as yellow oil

Step 5: Preparation of (R)-methyl1-(4-fluorophenylsulfonyl)-2-(hydroxymethyl)pyrrolidine-2-carboxylate.

A mixture of methyl(2R)-2-[(benzyloxy)methyl]-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylate(510 mg, 1.3 mmol), 10% palladium carbon (100 mg) in methanol (30 mL)was stirred for 18 h at room temperature under an atmosphere of hydrogengas. The solids were filtered off and the filtrate was concentratedunder reduced pressure to afford the title compound (400 mg) as lightyellow oil, which was used in the next step without any furtherpurification.

Step 6: Preparation of(R)-1-(4-fluorophenylsulfonyl)-2-(hydroxymethyl)pyrrolidine-2-carboxylicacid.

A mixture of methyl(2R)-1-[(4-fluorobenzene)sulfonyl]-2-(hydroxymethyl)pyrrolidine-2-carboxylate(40 mg, 0.13 mmol), LiOH (30 mg, 1.25 mmol) in methanol (1 mL), water (1mL) was stirred for 18 h at room temperature. The solution was acidified(pH-5) with 2 N HCl and concentrated under reduced pressure. Theresulting solution was extracted with EtOAc (3×10 mL), and the organiclayers were combined, dried (Na₂SO₄) and concentrated under reducedpressure to afford the title compound (40 mg) as a light yellow syrup,which was used in the next step without any further purification.

Step 7: Preparation of(2R)-1-(4-fluorophenylsulfonyl)-2-(hydroxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A solution of(2R)-1-[(4-fluorobenzene)sulfonyl]-2-(hydroxymethyl)pyrrolidine-2-carboxylicacid (40 mg, 0.13 mmol), HATU (62.7 mg, 0.16 mmol), DIPEA (57 mg, 0.44mmol) and [6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (32 mg, 0.11 mmol) in DMF (2 mL) was stirred for 2 h atroom temperature. The resulting solution was diluted with water (10 mL),extracted with EtOAc (3×). The combined organic layers were washed withbrine (3×), dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude product (70 mg) was purified by Prep-HPLC high pH to afford thetitle compound (24.7 mg) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ9.47 (s, 1H), 9.28 (s, 1H), 8.78 (d, J=8 Hz, 1H), 8.57-8.56 (m, 1H),8.25 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.96-7.92 (m, 2H), 7.38 (t, J=8.8Hz, 2H), 5.20-5.17 (m, 1H), 4.59-4.57 (m, 1H), 4.47-4.46 (m, 1H),4.06-4.03 (m, 1H), 3.87-3.85 (m, 1H), 3.53-3.52 (m, 1H), 3.24-3.22 (m,1H), 2.34-2.33 (m, 1H), 2.04-1.90 (m, 3H).

Example 8 Preparation of (2S,4R)-4-fluoro-N-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridine-4-carbaldehyde.

A mixture of 2-bromo-5-fluoropyridine-4-carbaldehyde (300 mg, 1.47mmol), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (420 mg, 2.20mmol), Pd(dppf)Cl₂.CH₂Cl₂ (60 mg, 0.07 mmol), Cs₂CO₃ (1.44 g, 0.09 mmol)in water (2 mL) and 1,4-Dioxane (6 mL) was stirred overnight at 90° C.in an oil bath under nitrogen. The resulting mixture was quenched withwater (20 mL), extracted with CH₂Cl₂ (3 ×) and separated. The combinedorganic layers were washed with brine (50 mL), dried (Na₂SO₄) andconcentrated under reduce pressure. The residue was purified by flashchromatography on silica gel with EtOAc/petroleum ether (12:88) toafford the title compound (110 mg) as a light yellow solid.

Step 2: Preparation of(5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methanamine.

A mixture of5-fluoro-2-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbaldehyde (363mg, 1.34 mmol), NH₂OH.HCl (187 mg, 2.69 mmol) in ethanol (15 mL) andwater (3 mL) was stirred for 30 min at 25° C. Then concentrated HCl(0.08 mL, 36%), Pd/C (300 mg, 10%) was added and the reaction mixturewas stirred for 50 min at 25° C. under an atmosphere of hydrogen gas.The solids were filtered off and the filtrate was concentrated underreduced pressure. The resulting mixture was diluted with H₂O (20 mL),and adjusted to pH ˜7-8 with 5 N NaHCO₃, extracted with EtOAc (3×). Thecombined organic layers were washed with brine (50 mL), dried (Na₂SO₄)and concentrated under reduced pressure to afford the crude titlecompound (300 mg) as yellow oil, which was used in the next step withoutany further purification.

Step 3: Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (129 mg, 0.44 mmol), HATU (169 mg, 0.44 mmol), DIPEA (143 mg, 1.11mmol),[5-fluoro-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methanamine(100 mg, 0.37 mmol) in DMF (2 mL) was stirred for overnight at 25° C.The reaction mixture was quenched with water (20 mL), extracted withdichloromethane (3×). The combined organic layers were washed with brine(20 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (6:4). The crude product was recrystallized frommethanol to afford the title compound (67 mg) as an off-white solid.¹H-NMR (300 MHz, CD₃OD) δ 9.08 (s, 1H), 8.61 (d, J=3 Hz, 1H), 8.43 (d,J=6 Hz, 1H), 8.02-7.92 (m, 4H), 7.38-7.32 (m, 2H), 5.16 (d, J=54 Hz,1H), 4.65 (s, 2H), 4.31-4.26 (m, 1H), 3.86-3.68 (m, 2H). 2.54-2.52 (m,1H), 2.32-2.06 (m, 1H).

Example 9 Preparation of (2S,4R)-4-fluoro-N-((5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2′-chloro-5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridine

A mixture of 2-chloro-5-fluoro-4-iodopyridine (2.57 g, 9.98 mmol),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (2.00 g, 10.48 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (407.63 mg, 0.50 mmol), sodium carbonate (2.12 g,20.00 mmol) in water (10 mL) and toluene (25 mL) was stirred forovernight at 90° C. under nitrogen. The reaction mixture wasconcentrated under reduced pressure, diluted with water (100 mL),extracted with dichloromethane (2×100 mL), and separated. The combinedorganic layers were washed with brine (200 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:5) toafford the title compound (2.31 g) as colorless oil.

Step 2: Preparation of5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridine-2′-carbonitrile.

A mixture of2-chloro-5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine (1 g, 3.62mmol), Pd₂(dba)₃.CHCl₃ (187 mg, 0.18 mmol), Zn(CN)₂ (254 mg, 2.16 mmol),DPPF (200 mg, 0.36 mmol), and Zn (24 mg, 0.37 mmol) in DMA (10 mL) wasirradiated with microwave radiation for 1 h at 125° C. under nitrogen.The reaction was then quenched withwater (100 mL), extracted with EtOAc(3×100 mL). The organic layers were combined and washed with brine (100mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1:5) to afford the title compound (860 mg) as ayellow solid.

Step 3: Preparation of(5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methanamine.

A mixture of5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile (250mg, 0.94 mmol), Raney Ni (100 mg, 1.17 mmol) in methanol (10 mL) wasstirred for 1 h at room temperature under an atmosphere of hydrogen. Thesolids were filtered off and the filtrate was concentrated under reducedpressure to afford the crude title compound (250 mg) as brown oil, whichwas used in the next step without any further purification.

Step 4: Preparation of(2S,4R)-4-fluoro-N-((5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of[5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(141 mg, 0.52 mmol), HATU (231 mg, 0.61 mmol), DIPEA (157 mg, 1.21mmol),(3R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-3-carboxylicacid (110 mg, 0.38 mmol) in DMF (5 mL) was stirred overnight at 25° C.The reaction mixture was quenched with water (20 mL), extracted withCH₂Cl₂ (3×20 mL). The combined organic layers were washed with brine (20mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residuewas purified by Prep-HPLC to afford the title compound (32.4 mg) as awhite solid. ¹H-NMR (300 MHz, CD₃OD) δ 9.41 (s, 1H), 8.72 (d, J=9.9 Hz,2H), 8.58 (d, J=1.2 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 8.04-7.99 (m, 2H),7.86 (d, J=8.4 Hz, 1H), 7.37-7.31 (m, 2H), 5.16 (d, J=51.9 Hz, 1H),4.74-4.56 (m, 2H), 4.33-4.27 (m, 1H), 3.86-3.67 (m, 2H), 2.54-2.52 (m,1H), 2.30-2.12 (m, 1H).

Example 10 Preparation of (2S,4R)-N-((6-(4-cyclopropylphenyl)pyrimidin-4-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (155.2 mg, 0.53 mmol), HATU (253.3 mg, 0.67 mmol), DIPEA (172 mg,1.33 mmol), [6-(4-cyclopropylphenyl)pyrimidin-4-yl]methanamine (100 mg,0.44 mmol) in DMF (5 mL) was stirred overnight at 25° C. The reactionmixture was quenched with water (20 mL), extracted with CH₂Cl₂ (3×) andseparated. The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by Prep-HPLC to afford the title compound (36.4 mg)as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ 8.94 (s, 1H), 8.04 (d, J=8Hz, 3H), 7.94-7.90 (m, 2H), 7.26-7.21 (m, 2H), 7.05 (d, J=8.4 Hz, 2H),5.06 (d, J=52 Hz, 1H), 4.48 (dd, J=17.6, 8.8 Hz, 2H), 4.23-4.18 (m, 1H),3.76-3.63 (m, 2H), 2.43-2.39 (m, 1H), 2.17-2.04 (m, 1H), 1.86-1.81 (m,1H), 0.92-0.90 (m, 2H), 0.65-0.63 (m, 2H).

Example 11 Preparation of (2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of4-chloro-6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidine.

A mixture of 4,6-dichloropyrimidine (2 g, 13.42 mmol), DIPEA (0.65 mL,3.93 mmol), 4-(trifluoromethyl)piperidine (9.74 g, 63.60 mmol) in DMF(20 mL) was stirred for 3 h at 25° C. The reaction mixture was thenquenched with water (100 mL), extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with water (3x) and brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (3:7) to afford the title compound (3.4 g) as awhite solid.

Step 2: Preparation of6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidine-4-carbonitrile.

A mixture of 4-chloro-6-[4-(trifluoromethyl)piperidin-1-yl]pyrimidine(2.6 g, 9.79 mmol), Pd₂(dba)₃.CHCl₃ (506 mg, 0.49 mmol), Zn(CN)₂ (686mg, 5.84 mmol), DPPF (540 mg, 0.97 mmol), and Zn (64 mg, 0.98 mmol) inDMA (26 mL) was irradiated with microwave radiation for 1 h at 125° C.under nitrogen. The reaction mixture was then quenched with water (100mL), extracted with EtOAc (3×100 mL). The combined organic layers werewashed with water (3×) and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel with EtOAc/petroleum ether (35:65) toafford the title compound (3.4 g) as a light yellow solid.

Step 3: Preparation of(6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)methanamine

A mixture of6-[4-(trifluoromethyl)piperidin-1-yl]pyrimidine-4-carbonitrile (500 mg,1.95 mmol), 10% Pa/C (500 mg), conc. HCl (0.2 mL) in methanol (10 mL)was stirred for 20 min at 25° C. under an atmosphere of hydrogen gas.The solids were filtered off and the mixture was concentrated underreduced pressure to afford the crude title compound (500 mg) as purpleoil, which was used in the next step without any further purification.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of[6-[4-(trifluoromethyl)piperidin-1-yl]pyrimidin-4-yl]methanamine (178.7mg, 0.69 mmol),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (200 mg, 0.69 mmol), HOBT (102 mg, 0.75 mmol), EDC.HCl (213 mg,1.11 mmol) and DIPEA (117.2 mg, 0.91 mmol), in DMF (5 mL) was stirredovernight at 25° C. The reaction mixture was quenched with water (20mL), extracted with EtOAc (3×20 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (85:15) to affordthe crude product (101 mg), which was then purified by Prep-HPLC toafford the title compound (45.5 mg) as a white solid. ¹H-NMR (400 MHz,CD₃OD) δ 8.42 (s, 1H), 8.04-8.01 (m, 2H), 7.39-7.35 (m, 2H), 7.05 (s,1H), 5.15 (d, J=39 Hz, 1H), 4.74 (m, 2H), 4.44-4.27 (m, 3H), 3.84-3.73(m, 2H), 3.00-2.94 (m, 2H), 2.56-2.51 (m, 2H), 2.40-2.11 (m, 1H),1.88-1.82 (m, 2H), 1.50-1.43 (m, 2H).

Example 12 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)cyclohex-1-enyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanol.

NaBH₄ (76 mg, 2.01 mmol) was added portionwise to a solution of ethyl6-[4-(trifluoromethyl) cyclohex-1-en-1-yl]pyrimidine-4-carboxylate (300mg, 1.00 mmol) in methanol (10 mL) with stirring. The resulting mixturewas stirred for 2 h at 25° C., and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith EtOAc/petroleum ether (1:1) to afford the title compound (254 mg)as a white solid.

Step 2: Preparation of 2-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H- isoindole-1,3-dione.

DIAD (235 mg, 1.16 mmol) was added dropwise to a solution of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanol (150mg, 0.58 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (94 mg, 0.64 mmol),PPh₃ (305 mg, 1.16 mmol) in THF (10 mL) at 0° C. with stirring. Theresulting mixture was stirred for 2 h at 25° C., then diluted with water(20 mL), extracted with dichloromethane (3 ×20 mL). The organic layerswere combined and washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with EtOAc/petroleum ether(1:1) to afford the title compound (425 mg) as a white solid.

Step 3: Preparation of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanamine.

A mixture of2-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(425 mg, 1.10 mmol), hydrazine hydrate (80%) (0.5 mL) in methanol (10mL) was stirred for 3 h at 25° C., and concentrated under reducedpressure. The residue was dissolved in EtOAc (3 mL), and the solids werefiltered out. The filtrate was concentrated under reduced pressure toafford the crude title compound (210 mg) as a white solid, which wasused in the next step without any further purification.

Step 4: Preparation of (2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)cyclohex-1-enyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanamine(284 mg, 1.10 mmol), HATU (465.8 mg, 1.23 mmol), DIPEA (317 mg, 2.45mmol) in DMF (5 mL) was stirred for 10 min at 25° C. Then(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (210 mg, 0.72 mmol) was added and the resulting mixture was astirred overnight at 25° C. The reaction mixture was then quenched withwater (10 mL), extracted with dichloromethane (3×10 mL). The combinedorganic layers were washed with brine (2×10 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product (120mg) was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, CH₃CN: H₂O from10% to 65% within 30 min; Detector, UV 254 nm to afford the titlecompound (25.8 mg) as a white solid. ¹H-NMR (300 MHz, CD₃OD) δ 8.99 (s,1H), 8.04 (q, J=6 Hz, 2H), 7.84 (s, 1H), 7.38 (t, J=9 Hz, 2H), 7.15 (s,1H), 5.16 (d, J=51 Hz, 1H), 4.88-4.86 (d, J=6 Hz, 2H), 4.31 (t, J=9 Hz,1H), 3.86-3.72 (m, 2H), 2.84 (m, 1H), 2.59-2.47 (m, 4H), 2.32-2.14 (m,3H), 1.67-1.61 (m, 1H).

Example 13 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-((1s,4R)-4-(trifluoromethyl)cyclohexyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamideand ((2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-((1r, 4S)-4(trifluoromethyl)cyclohexyl)-pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(180 mg, 0.34 mmol), 10% Pd(OH)₂/C (30 mg) in methanol (20 mL) wasstirred for 15 min at 25° C. under an atmosphere of hydrogen gas. Thesolids were filtered off and the filtrate was concentrated under reducedpressure. The residue (260 mg) was purified by Flash-Prep-HPLC with thefollowing conditions: Column, C18 silica gel; mobile phase, CH₃CN: H₂Ofrom 10% to 55% within 30 min; Detector, UV 254 nm to afford a mixtureof cis/trans-isomers (120 mg). The isomers were separated byChiral-Prep-HPLC with the following conditions (Prep-HPLC-004): Column,Chiralpak IA, 2*25 cm, 5 um; mobile phase, Hex and IPA (hold 30.0% IPAin 20 min); Detector, UV 254/220 nm.

Faster eluting isomer (33.6 mg) arbitrarily assigned as trans isomer(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[(1r,4S)-4-(trifluoromethyl)cyclohexyl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide: ¹H-NMR (300MHz, CD₃OD) δ 8.97 (s, 1H), 8.04 (q, J=6 Hz, 2H), 7.71 (s, 1H), 7.37 (t,J=9 Hz, 2H), 5.16 (d, J=54 Hz, 1H), 4.54 (s, 2H), 4.32 (t, J=9 Hz, 1H),3.86-3.72 (m, 2H), 2.72 (t, J=3 Hz, 1H), 2.51 (m, 1H), 2.27-2.04 (m,6H), 1.74-1.53 (m, 2H), 1.50-1.44 (m, 2H).

Slower eluting isomer (18 mg), arbitrarily assigned as cis isomer(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[(1s,4R)-4-(trifluoromethyl)cyclohexyl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide:¹H-NMR (300 MHz, CD₃OD) δ 9.02 (s, 1H), 8.01 (q, J=6 Hz, 2H), 7.74 (s,1H), 7.36 (t, J=9 Hz, 2H), 5.15 (d, J=54 Hz, 1H), 4.56 (d, J=3 Hz, 2H),4.27 (t, J=9 Hz, 1H), 3.86-3.72 (m, 2H), 3.03-3.00 (m, 1H), 2.53-2.51(m, 1H), 2.35-2.06 (m, 5H), 1.88-1.61 (m, 6H).

Example 14 Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(5-(trifluoromethyl)pyridin-2-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of ethyl 6-hydroxyl)yrimidine-4-carboxylate.

Triethylamine (19 g, 187.8 mmol) was added dropwise to a mixture of1,4-diethyl but-2-ynedioate (25 g, 146.92 mmol), methanimidamidehydrochloride (11.83 g, 146.93 mmol), CH₃CN (500 mL). The reaction wasstirred for 2.5 h at 80° C. in an oil bath and then cooled to 5° C. Thecrude products were collected by filtration and re-crystallized fromCH₃CN to afford the title compound (18.0 g, 73%) as a white solid.

Step 2: Preparation of ethyl 6-chloropyrimidine-4-carboxylate.

To a mixture of ethyl 6-hydroxyl)yrimidine-4-carboxylate (5.0 g, 29.74mmol), EtOAc (150 mL) and N,N-dimethylformamide (0.2 mL) was added(COCl)₂ (11.3 g, 89.03 mmol) dropwise with stirring. The reaction wasstirred overnight at 75° C. The reaction was cooled and the solids werefiltered off The filtrate was concentrated and purified by a flashchromatography on a silica gel eluting with petroleum ether:EtOAc(10:1-5:1) to afford the title compound (2.2 g, 40%) as a light yellowsolid.

Step 3: Preparation of ethyl6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidine-4-carboxylate.

A mixture of 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (8.4 g,19.26 mmol), Pd(PPh₃)₂Cl₂ (558 mg, 0.79 mmol), CuI (168 mg, 0.88 mmol),and ethyl 6-chloropyrimidine-4-carboxylate (900 mg, 4.82 mmol) in DMF(72 mL) was irradiated with microwave radiation for 30 min at 60° C.under nitrogen. The reaction was diluted EtOAc (300 mL), washed withbrine (2x), dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by flash chromatography on a silica gel eluting withEtOAc/petroleum (10/1) to afford the title compound (300 mg, 21%) as ayellow solid.

Step 4: Preparation of[6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methanol.

NaBH₄ (55 mg, 1.45 mmol) was added to a mixture of ethyl6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidine-4-carboxylate (290 mg,0.98 mmol) in THF (30 mL) in portionwise at 0-5° C. The reaction wasstirred for 0.5 h at room temperature. The reaction was then quenchedwith the addition of water (50 mL) at 0-5° C., extracted with EtOAc(3×50 mL), washed with brine (3×30 mL), dried over anhydrous Na2SO4 andconcentrated. The residue was purified by flash chromatography on asilica gel eluting with petroleum ether:EtOAc (5:1) to afford the titlecompound (216 mg , 87%) as a light yellow solid.

Step 5: Preparation of2-([6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione.

DIAD (326 mg, 1.61 mmol) was added dropwise into a mixture of[6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methanol (206 mg,0.81 mmol), THF (20 mL), PPh₃ (423 mg, 1.61 mmol) and2,3-dihydro-1H-isoindole-1,3-dione (142 mg, 0.97 mmol) with stirring at0° C. The reaction was stirred for 2 h at room temperature andconcentrated. The residue was purified by flash chromatography on asilica gel eluting with petroleum ether:EtOAc (20:1) to afford the titlecompound (300 mg , 97%) as a white solid.

Step 6: Preparation of[6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methanamine.

A mixture of2-([6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(290 mg, 0.75 mmol), methanol (15 mL) and hydrazine hydrate (472 mg,9.43 mmol) was stirred for 4 h at 40° C. The mixture was concentrated,diluted with water (20 mL), extracted with EtOAc (3×30 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, concentrated to affordthe title compound (360 mg) as a green solid, which was used in the nextstep without any further purification.

Step 7: Preparation of(2S)-1-[(4-fluorobenzene)sulfonyl]-2-methyl-N-([6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

A mixture of(2S)-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylic acid(190 mg, 0.66 mmol), N,N-dimethylformamide (5 mL), DIPEA (213 mg, 1.65mmol, 3.00 equiv), HATU (314 mg, 0.83 mmol) and[6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-yl]methanamine (140 mg,0.55 mmol) was stirred overnight at room temperature. The crude solutionwas purified directly by Prep-HPLC to afford the title compound (7.6 mg,3%) as a white solid. ¹H-NMR (300MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.17 (s,1H), 8.69 (d, J=3 Hz, 1H), 8.60-8.57 (m, 1H), 8.53-8.50 (m, 1H), 8.49(s, 1H), 8.01-7.96 (m, 2H), 7.50-7.44 (m, 2H), 4.58-4.55 (m, 2H),3.70-3.50 (m, 2H), 2.31-2.26 (m, 1H), 2.06-1.95 (m, 3H), 1.58 (s, 3H),1.40-1.20 (m, 1H).

Example 15 Preparation of(2S,4R)-N-([3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-pyrrolidine-2-carboxylicacid (48 mg, 0.16 mmol), DIPEA (63 mg, 0.49 mmol), DMF (3 mL), HATU (94mg, 0.25 mmol) and[3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine(46 mg, 0.17 mmol) was stirred for 2 h at room temperature. The reactionmixture was purified directly by Prep-HPLC to afford the title compound(40 mg, 44%) as a white solid. ¹H-NMR (300 MHz, CD₃OD) δ 9.16 (s, 1H),8.55 (s, 1H), 8.33-8.37 (m, 1H), 7.94-8.02 (m, 3H), 7.32-7.38 (m, 2H),5.15 (d, J=52.5 Hz, 1H), 4.39 (s, 2H), 4.25-4.19 (m, 1H), 3.85-3.67 (m,2H), 2.53-2.42 (m, 1H), 2.29-2.10 (m, 1H).

Example 16 Preparation of(2S,4R)-N-([3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-pyrrolidine-2-carboxylicacid (100 mg, 0.34 mmol), DMF (2 mL), DIPEA (132 mg, 1.02 mmol), HATU(194 mg, 0.51 mmol) and[3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine (187mg, 0.68 mmol) was stirred for 2 h at room temperature. The reactionmixture was purified directly by Prep-HPLC to afford the title compound(38 mg, 20%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H),8.00-7.79 (m, 6H), 7.42-7.31 (m, 2H), 5.14 (d, J=52 Hz, 1H), 4.37 (s,2H), 4.30-4.19 (m, 1H), 3.87-3.69 (m, 3H), 2.52-2.43 (m, 1H), 2.25-2.08(m, 1H).

Example 17 Preparation of(2S,4R)-N-([3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-(cyclopropanecarbonyl)-3-ethoxyprop-2-enenitrile.

A mixture of 3-cyclopropyl-3-oxopropanenitrile (5.5 g, 50.40 mmol),(diethoxymethoxy)ethane (74.7 g, 504.05 mmol), acetic anhydride (60 mL,634.74 mmol) was stirred for 2 h at 150° C. The mixture was cooled,concentrated under reduced pressure. The residue was recrystallized fromethanol to afford the title compound (6 g, 72%) as a light yellow solid.

Step 2: Preparation of 3-cyclopropyl-1H-pyrazole-4-carbonitrile.

A mixture of 2(cyclopropanecarbonyl)-3-ethoxyprop-2-enenitrile (2 g,12.11 mmol), hydrazine hydrate (85%) (6.1 g, 121.85 mmol) and ethanol(20 mL) was stirred for 10 min at room temperature. The mixture wasconcentrated under reduced pressure. The residue was re-crystallizedfrom toluene to afford the title compound (1 g, 62%) as a yellow solid.

Step 3: Preparation of3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbonitrile.

A mixture of 3-cyclopropyl-1H-pyrazole-4-carbonitrile (1 g, 7.51 mmol),5-bromo-2-(trifluoromethyl)pyridine (2.88 g, 12.74 mmol), CuI (143 mg,0.75 mmol), L-proline (173 mg, 1.50 mmol), potassium carbonate (2.28 g,16.50 mmol) and DMSO (50 mL) was stirred for 12 h at 100° C. undernitrogen. The mixture was cooled, diluted with EtOAc (200 mL), washedwith brine (3×100 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel eluting with petroleum ether/EtOAc (50/1) to afford thetitle compound (1.1 g, 53%) as a white solid.

Step 4: Preparation of[3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine.

A mixture of3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbonitrile(1 g, 3.59 mmol), methanol (50 mL) and RaneyNi (500 mg, 5.84 mmol) wasstirred for 15 min at room temperature under an atmosphere of hydrogengas. The solids were filtered off, and the filtrate was concentratedunder reduced pressure to afford the title compound (900 mg) as a whitesolid, which was used in the next step without any further purification.

Step 5: Preparation of(2S,4R)-N-([3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (80 mg, 0.27 mmol), DMF (5 mL), DIPEA (106.8 mg, 0.83 mmol), HATU(156.6 mg, 0.41 mmol) and3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-ylmethanamine(77.55 mg, 0.27 mmol) was stirred for 1 h at room temperature. The crudesolution was purified directly by Prep-HPLC to afford the title compound(50 mg, 33%) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.66 (s, 1H), 8.49 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.02-7.96 (m, 3H),7.74 (m, 1H), 5.27-5.10 (m, 1H), 4.33-4.30 (m, 2H), 4.19-4.14 (m, 1H),3.71-3.67 (m, 1H), 3.62-3.58 (m, 1H), 2.51 (m, 1H), 2.42-2.29 (m, 1H),2.18-1.94 (m, 1H), 0.96-0.90 (m, 4H).

Example 18 Preparation of(2S,4R)-N-([3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-1-[(4-cyanobenzene)sulfonyl]-4-fluoropyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-1-[(4-cyanobenzene)sulfonyl]-4-fluoropyrrolidine-2-carboxylicacid

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (79 mg, 0.59mmol), tetrahydrofuran (5 mL), water (2 mL), sodium carbonate (121 mg,1.13 mmol) and 4-cyanobenzene-1-sulfonyl chloride (100 mg, 0.50 mmol)was stirred for 1 h at 0° C. The mixture was diluted with water,extracted with ether (30 mL). The aqueous layers was acidified with 3 NHCl to pH=2-3, extracted with EtOAc (3×50 mL). The combined organiclayers were dried over anhydrous Na2SO4 and concentrated to afford thetitle compound (100 mg, 68%) as a white solid, which was used in thenext step without any further purification.

Step 2: Preparation of(2S,4R)-N-([3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-1-[(4-cyanobenzene)sulfonyl]-4-fluoropyrrolidine-2-carboxamide.

A mixture of(2S,4R)-1-[(4-cyanobenzene)sulfonyl]-4-fluoropyrrolidine-2-carboxylicacid (180 mg, 0.60 mmol), N,N-dimethylformamide (5 mL), DIPEA (234 mg,1.81 mmol), HATU (234 mg, 0.62 mmol) and[3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine (234mg, 0.85 mmol) was stirred overnight at room temperature. The reactionmixture was purified by Prep-HPLC to afford the title compound (85.1 mg,25%) as a white solid. ¹H-NMR (300MHz, DMSO-d₆) δ 8.74 (m, 1H), 8.60 (s,1H), 8.12-8.04 (m, 4H), 7.99-7.88 (m, 4H), 5.20 (d, J=51.9 Hz, 1H),4.21-4.17 (m, 3H), 3.85-3.55 (m, 2H), 2.77-2.33 (m, 1H), 2.19-1.98 (m,1H).

Example 19 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-Butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate.

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(2 g, 8.57 mmol), potassium carbonate (5.9 g, 42.69 mmol), THF (80 mL)and CH₃I (6.1 g, 42.98 mmol) was stirred for 12 h at room temperature.The solids were filtered off and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with EtOAc/petroleum ether (1:5) to afford the titlecompound (800 mg, 38%) as colorless oil.

Step 2: Preparation of 1-tert-butyl 2-methyl(4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate.

A 1 M solution of LiHMDS (4.85 mL, 4.85 mmol) was added dropwise into amixture of 1-tert-butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (400 mg, 1.62 mmol) in THF(20 mL) with stirring at −78° C. under nitrogen. The reaction solutionwas stirred for 30 min at −78° C. To this was added CH₃I (690 mg, 4.86mmol) dropwise at −78° C. The reaction mixture stirred for 12 h at roomtemperature, quenched with water (20 mL), extracted with EtOAc (3×30mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1:5) to afford the title compound (360 mg, 85%)as colorless oil.

Step 3: Preparation of 4R-4-fluoro-2-methylpyrrolidine-2-carboxylic acidhydrochloride.

A mixture of 1-tert-butyl 2-methyl(4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate (360 mg, 1.38 mmol)and HCl in dioxane (10 mL, 1 mol/L) was stirred for 2 h at roomtemperature. The mixture was concentrated to afford the crude product(315 mg) as a light yellow solid, which was used in the next stepwithout any further purification.

Step 4: Preparation of methyl(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylate.

A mixture of 4R-4-fluoro-2-methylpyrrolidine-2-carboxylate hydrochloride(315 mg, 1.60 mmol), triethylamine (485 mg, 4.80 mmol), dichloromethane(20 mL) and 4-fluorobenzene-1-sulfonyl chloride (310 mg, 1.60 mmol) wasstirred for 12 h at room temperature. The reaction was diluted withdichloromethane (100 mL), washed with brine (3×20 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:4) toafford the title compound (380 mg) as colorless oil, which was used inthe next step without any further purification.

Step 5: Preparation of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid.

A mixture of methyl(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylate(380 mg, 1.19 mmol), LiOH (58 mg, 2.42 mmol), methanol (8 mL), water (2mL) was stirred for 12 h at room temperature. The reaction mixture wasconcentrated, dissolved in water (20 mL), extracted with ether (3×20mL). The aqueous layers was acidified with 3 N HCl (pH 2-3), extractedwith EtOAc (3×50 mL), dried over anhydrous Na₂SO₄ and concentrated toafford the title compound (260 mg, 72%) as yellow oil, which was used inthe next step without any further purification.

Step 6: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (125 mg, 0.41 mmol), DMF (4 mL), HATU (228 mg, 0.60 mmol), DIPEA(206 mg, 1.59 mmol) and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (104 mg, 0.36 mmol) was stirred for 12 h at roomtemperature. The mixture was diluted with water (20 mL), extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on silica gel eluting with EtOAc/petroleum ether(1:1 to 2:1).

Slower eluting isomer (72.7 mg) was assigned by potency as(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide:¹H-NMR (300 MHz, CD₃OD) δ 9.50 (s, 1H), 9.20 (s,1H), 8.83 (d, J=8.4 Hz,1H), 8.31 (s, 1H), 8.06-7.98 (m, 3H), 7.37 (t, J=17.4 Hz, 2H), 5.26 (d,J=51 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.19-4.07(m, 1H), 3.76-3.60 (m, 1H), 2.76-2.64 (m, 1H), 2.33-2.14 (m, 1H),1.61(s, 3H).

Example 20 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (125 mg, 0.41 mmol), DMF (4 mL), HATU (234 mg, 0.62 mmol), DIPEA(212 mg, 1.64 mmol) and[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine hydrochloride(106 mg, 0.37 mmol) was stirred for 12 h at room temperature. Themixture was diluted with water (20 mL), extracted with EtOAc (3×50 mL),washed with brine (3×20 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel eluting with EtOAc/petroleum ether (1:1).

Faster eluting isomer (24.8 mg)(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide:¹H-NMR (300 MHz, CD₃OD) δ 9.19 (d, J=1.2 Hz, 1H), 8.45 (d, J=7.8 Hz,2H), 8.34 (s, 1H), 8.05-8.01 (m, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.32 (t,J=8.7 Hz, 2H), 5.30 (d, J=51.9 Hz, 1H), 4.71-4.51 (m, 2H), 3.94-3.90 (m,1H), 3.82 (d, J=2.4 Hz, 1H), 2.72-2.34 (m, 2H), 1.82 (s, 3H).

Example 21 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine.

A mixture of 4,6-dichloropyrimidine (2.17 g, 14.57 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (1 g, 4.86 mmol), Pd(dppf)Cl₂(731 mg, 1.00 mmol), potassium carbonate (5 g, 36.18 mmol), dioxane (40mL) and water (4 mL) was stirred for 12 h at 100° C. under nitrogen. Themixture was diluted with EtOAc (150 mL), washed with brine (3×), driedand concentrated. The residue was purified by flash chromatography onsilica gel eluting with EtOAc/petroleum ether (1/50) to afford the titlecompound (1.1 g, 82%) as a white solid.

Step 2: Preparation of6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile.

A mixture of 4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine (820 mg,2.99 mmol), Zn(CN)₂ (421 mg, 3.58 mmol), Pd(PPh₃)₄ (347 mg, 0.30 mmol),DMF (6 mL) was stirred for 9 h at 100° C. under nitrogen. The reactionwas cooled, diluted with water (30 mL), extracted with EtOAc (3×50 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/50)to afford the title compound (320 mg, 40%) as a white solid.

Step 3: Preparation of(6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methanamine hydrochloride.

A mixture of 6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile(160 mg, 0.60 mmol), ethanol (10 mL), concentrated HCl solution (0.02mL), 10% Palladium over carbon (100 mg) was stirred for 10 min at roomtemperature under an atmosphere of hydrogen gas. The solids werefiltered off and the filtrate was concentrated to afford the crudeproduct (200 mg) as a solid, which was used in the next step without anyfurther purification.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrro-lidine-2-carboxylicacid (150 mg, 0.51 mmol), DMF (4 mL), DIPEA (263 mg, 2.03 mmol), HATU(294 mg, 0.77 mmol) and[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanamine (200 mg, 0.74mmol) was stirred for 12 h at room temperature. The crude solution waspurified directly by Prep-HPLC to afford the title compound (51 mg, 13%)as a white solid. ¹H-NMR (300 MHz, CD₃OD) δ 9.15 (s, 1H), 8.41 (d, J=8.7Hz, 6H), 8.25 (s, 1H), 8.08-8.03 (m, 2H), 7.40-7.34 (m, 4H), 5.17 (d,J=51.6 Hz, 1H), 4.63 (d, J=4.8 Hz, 2H), 4.37-4.31 (m, 1H), 3.88-3.75 (m,2H), 2.61-2.48 (m, 1H), 2.35-2.11 (m, 1H).

Example 22 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((2-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of4-chloro-2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine.

A mixture of 4,6-dichloro-2-methylpyrimidine (1 g, 6.13 mmol),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (229 mg, 1.20 mmol),potassium carbonate (2.07 g, 14.98 mmol), dioxane (50 mL), water (2 mL)and Pd(dppf)Cl₂ (320 mg, 0.44 mmol) was irradiated with microwaveradiation for 3 h at 100° C. under nitrogen. The mixture was dilutedwith EtOAc (150 mL), washed with brine (3×50 mL), dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/10)to afford the title compound (1.1 g, 66%) as a white solid.

Step 2: Preparation of2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carbonitrile.

A mixture of4-chloro-2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine (300 mg,1.10 mmol), DMF (5 mL), Zn(CN)₂ (128.7 mg, 1.10 mmol), dppf (60.9 mg,0.11 mmol) and Pd₂(dba)₃CHCl₃ (113.9 mg, 0.11 mmol) was irradiated withmicrowave radiation for 3 h at 120° C. under nitrogen. The mixture wasdiluted with EtOAc (100 mL), washed with brine (3x), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/10)to afford the title compound (250 mg, 86%) as a white solid.

Step 3: Preparation of[2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrogen chloride.

A mixture of2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carbonitrile(250 mg, 0.94 mmol), ethanol (20 mL), concentrated HCl (0.2 mL) and 10%Palladium carbon (200 mg) was stirred for 5 min at room temperatureunder an atmosphere of hydrogen gas. The solids were filtered off andthe filtrate was concentrated to afford the crude product (200 mg) as ablack solid, which was used in the next step without any furtherpurification.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((2-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (107.7 mg, 0.37 mmol), DMF (5 mL), DIPEA (144.4 mg, 1.12 mmol),HATU (212.8 mg, 0.56 mmol) and[2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrogen chloride (112 mg, 0.37 mmol) was stirred for 1 h at roomtemperature. The crude solution was purified directly by Prep-HPLC toafford the title compound (32.9 mg, 16%) as a white solid.¹H-NMR (300MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.69 (d, J=7.2 Hz, 1H), 7.94-7.91 (m, 3H),7.89 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.28-7.23 (m, 1H), 5.09 (d, J=52.2Hz ,1H), 4.94-4.89 (m, 1H), 4.50-4.45 (m ,1H), 4.37-4.31 (m, 1H),3.96-3.62 (m, 2H), 2.83 (s, 3H), 2.64-2.54 (m, 1H), 2.34-1.52 (m, 1H).

Example 23 Preparation of(2S,4R)-N-((6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2-cyclopropyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

A mixture of 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3 ,2-dioxaborolane (2.7 g, 10.63 mmol),Pd(dppf)Cl₂ (519 mg, 0.71 mmol), KOAc (1.39 g, 14.16 mmol), 1,4-dioxane(100 mL) and 5-bromo-2-cyclopropylpyridine (1.4 g, 7.07 mmol) wasstirred for 6 h at 90° C. under nitrogen. The mixture was concentratedand purified by flash chromatography on a silica gel eluting withpetroleum ether/EtOAc (10/1) to afford the title compound (1.5 g, 87%)as brown oil.

Step 2: Preparation of6-(6-cyclopropylpyridin-3-yl)pyrimidine-4-carboxylic acid.

A mixture of2-cyclopropyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.5 g,6.12 mmol), ethyl 6-chloropyrimidine-4-carboxylate (1.3 g, 6.97 mmol),Pd(PPh₃)₄ (1.04 g, 0.90 mmol), K₃PO₄ (3.18 g, 14.98 mmol), 1,4-dioxane(100 mL) and water (10 mL) was stirred overnight at 65° C. undernitrogen. The mixture was concentrated, diluted with water (50 mL),acidified with 3 N HCl (pH 2-3), extracted with EtOAc (3×100 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to afford the title compound (2.6 g) as a brown solid,which was used in the next step without any further purification.

Step 3: Preparation of methyl6-(6-cyclopropylpyridin-3-yl)pyrimidine-4-carboxylate.

A mixture of 6-(6-cyclopropylpyridin-3-yl)pyrimidine-4-carboxylic acid(2.6 g, 10.78 mmol), methanol (60 mL, 1.48 mol), concentrated H₂SO₄ (0.5mL, 98%) was stirred overnight at 70° C. The mixture was concentratedunder reduced pressure, dissolved with EtOAc (150 mL), washed withsaturated NaHCO₃ (3×30 mL), dried over anhydrous Na₂SO₄ and concentratedto afford the title compound (310 mg) as a brown solid, which was usedin the next step without any further purification.

Step 4: Preparation of[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methanol.

NaBH₄ (136 mg, 3.69 mmol) was added into a solution of6-(6-cyclopropylpyridin-3-yl)pyrimidine-4-carboxylate (310 mg, 1.21mmol) and methanol (10 mL) with stirring at room temperature. Thereaction was stirred for 30 min and quenched with water (20 mL),extracted with EtOAc (3×30 mL), washed with brine (3×20 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1) to afford the title compound (230 mg, 83%) as a brown solid.

Step 5: Preparation of2-[[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methyl]-2,3-dihydro-1H-isoindole-1,3-dione.

DIAD (266 mg, 1.32 mmol) was added dropwise into a mixture of[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methanol (100 mg, 0.44mmol), 2,3-dihydro-1H-isoindole-1,3-dione (98 mg, 0.67 mmol), PPh₃ (346mg, 1.32 mmol) and THF (10 mL) with stirring at 0° C. The resultingsolution was stirred for 5 h at room temperature. The mixture wasconcentrated under reduced pressure, and the residue was purified byflash chromatography on silica gel eluting with EtOAc/petroleum ether(1/1) to afford the title compound (102 mg, 65%) as a yellow solid.

Step 6: Preparation of[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methanamine

A mixture of2-[[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methyl]-2,3-dihydro-1H-isoindole-1,3-dione(102 mg, 0.29 mmol), methanol (20 mL) and hydrazine hydrate (140 mg,80%) was stirred for 5 h at 40° C. The resulting mixture wasconcentrated, diluted with 1 N HCl (20 mL), washed with EtOAc (30 mL).The aqueous layer was basified with 3 N NaOH (pH˜8-9), extracted withEtOAc (3×50 mL). The organic layer combined, dried over anhydrous Na₂SO₄and concentrated to afford the crude product (35 mg, 54%) as a yellowsolid, which was used in the next step without any further purification.

Step 7: Preparation of(2S,4R)-N-((6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (52 mg, 0.18 mmol), DMF(5 mL), DIPEA (38.7 mg, 0.30 mmol), HATU(85.5 mg, 0.22 mmol) and[6-(6-cyclopropylpyridin-3-yl)pyrimidin-4-yl]methanamine (35 mg, 0.15mmol) was stirred overnight at room temperature. The crude solution waspurified directly by Prep-HPLC to afford the title compound (16.5 mg,21%) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 2H), 9.39(d, J=9.0 Hz, 1H), 7.96-7.91 (m, 3H), 7.64 (d, J=9.0 Hz, 1H), 7.25 (t,J=3.9 Hz, 3H), 5.09 (d, J=51.9 Hz, 1H), 4.89-4.81 (m, 1H), 4.59-4.52 (m,1H), 4.34 (t, J=9 Hz, 1H), 3.98-3.63 (m, 2H), 2.66-2.52 (m, 1H),2.37-2.17 (m, 2H), 1.14-1.05 (m, 4H).

Example 24: Preparation of(2S,4R)-1-(5-chlorothiophen-2-ylsulfonyl)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine,Example 2, step 2 and Example 2, step 3 using5-chlorothiophene-2-sulfonyl chloride (50.9 mg) as a light yellow solid.¹H-NMR (300 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.30 (s, 1H), 9.12 (t, J=5.7Hz, 1H), 8.80-8.76 (m, 1H), 8.13 (t, J=8.1 Hz, 2H), 7.78 (s, 1H), 7.40(s, 1H), 5.27 (d, J=51 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.32-4.26 (m,1H), 3.86-3.75 (m, 1H), 3.70 (s, 1H), 2.59-2.47 (m, 1H), 2.29-2.06 (m,1H).

Example 25 Preparation of(2S,4R)-1-(3,4-difluorophenylsulfonyl)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine,Example 2, step 2 and Example 2, step 3 using3,4-difluorobenzene-1-sulfonyl chloride as a light yellow solid. ¹H-NMR(300 MHz, CDCl₃) δ 9.52 (s, 1H), 9.28 (s, 1H), 8.70 (d, J=7.8 Hz, 1H),8.09 (s, 1H), 7.83-7.68 (m, 3H), 7.61-7.58 (m, 1H), 7.42-7.33 (m, 1H),5.11 (d, J=51.6 Hz, 1H), 4.99-4.92 (m, 1H), 4.62-4.55 (m, 1H), 4.35 (t,J=9 Hz, 1H), 3.95-3.64 (m, 2H), 2.65-2.57 (m, 1H), 2.37-2.02 (m, 1H).

Example 26 Preparation of(2S,4R)-1-(3,4-difluorophenylsulfonyl)-4-fluoro-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, andExample 2, steps 2 and 3 using 3,4-difluorobenzene-1-sulfonyl chlorideas a white solid. ¹H-NMR (300 MHz, CDCl₃) δ 9.29 (s, 1H), 8.33 (d, J=8.1Hz, 2H), 8.08 (s, 1H), 7.82-7.61 (m, 5H), 7.41-7.33 (m, 1H), 5.11 (d,J=51.9 Hz, 1H), 4.95-4.88 (m, 1H), 4.71-4.65 (m, 1H), 4.33 (dd, J=7.4,9.9 Hz, 1H), 3.94-3.69 (m, 2H), 2.67-2.53 (m, 1H), 2.40-2.23 (m, 1H).

Example 27 Preparation of(2S,4R)-4-fluoro-1-(5-fluoropyridin-3-ylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine,Example 2, step 2 and Example 2, step 3 using5-fluoropyridine-3-sulfonyl chloride as a white solid. ¹H-NMR (300 MHz,DMSO-d₆) δ 9.49 (s, 1H), 9.31 (s, 1H), 9.20-9.10 (m, 1H), 9.01 (s, 1H),8.94 (d, J=2.7 Hz, 1H), 8.80 (m, 1H), 8.40 (m, 1H), 8.21 (d, J=2.7 Hz,1H), 8.10 (m, 1H), 5.24 (d, J=51.3 Hz, 1H), 4.40-4.38 (m, 2H), 4.36-4.33(m, 2H), 3.97-3.59 (m, 2H), 2.44-2.04 (m, 2H).

Example 28 Preparation of(2S,4R)-4-fluoro-1-(5-fluoropyridin-3-ylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, andExample 2, steps 2 and 3 using 5-fluoropyridine-3-sulfonyl chloride.¹H-NMR (300 MHz, CDCl₃) δ 9.26 (s, 1H), 8.94 (s, 1H), 8.75 (s, 1H), 8.29(d, J=8.1 Hz, 2H), 7.94-7.89 (m, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.61 (s,1H), 5.13 (d, J=51 Hz, 1H), 4.82 (m, 1H), 4.75 (m, 1H), 4.39 (m, 1H),4.29 (m, 1H), 3.97-3.6 (m, 2H), 2.63-2.2 (m, 2H).

Example 29 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethylthio)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (102 mg, 0.35 mmol), DMF(5 mL), DIPEA (136 mg, 1.05 mmol), HATU(200 mg, 0.53 mmol) and(6-[4-[(trifluoromethyl)sulfanyl]phenyl]pyrimidin-4-yl)methanamine (100mg, 0.35 mmol) was stirred for 1 h at room temperature. The crudesolution was purified directly by Prep-HPLC high to afford the titlecompound (75.4 mg, 39%) as a white solid. ¹H-NMR (300MHz, CD₃OD) δ 9.16(s, 1H), 8.39 (d, J=8.4 Hz, 2H), 8.27 (s, 1H), 8.07-8.01 (m, 2H), 7.79(d, J=8.4 Hz, 2H), 7.38-7.32 (m, 2H), 5.16 (d, J=51.9 Hz, 1H), 4.63 (d,J=4.2 Hz, 2H), 4.32 (dd, J=10.2, 7.2 Hz, 1H), 3.87-3.9 (m, 2H),2.57-2.15 (m, 2H).

Example 30 Preparation of(R)-1-(4-fluorophenylsulfonyl)-2-(methoxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-[(4-fluorobenzene) sulfonyl]-2-(methoxymethyl)pyrrolidine-2-carboxylic acid.

Sodium hydride (379 mg, 9.47 mmol, 60% in mineral oil) was added to asolution of methyl1-[(4-fluorobenzene)sulfonyl]-2-(hydroxymethyl)pyrrolidine-2-carboxylate(100 mg, 0.32 mmol), THF (7 mL). The mixture was stirred for 20 min atroom temperature, and CH₃I (222.8 mg, 1.57 mmol) was added. Theresulting solution was stirred for 2 h at room temperature. The reactionwas then quenched with 5% HCl (15 m), extracted with EtOAc (3×30 mL).The combined organic layers were dried over anhydrous Na₂SO₄,concentrated to afford the title compound (75 mg) as a white solid,which was used in the next step without any further purification.

Step 2: Preparation of(R)-1-(4-fluorophenylsulfonyl)-2-(methoxymethyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2R)-1-[(4-fluorobenzene)sulfonyl]-2-(methoxymethyl)pyrrolidine-2-carboxylicacid (70 mg, 0.22 mmol), DMF (2 mL), DIPEA (113.9 mg, 0.88 mmol), HATU(125.86 mg, 0.33 mmol) and [6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanamine hydrochloride (77.1 mg, 0.27mmol) was stirred for 12 h at room temperature. The reaction mixture waspurified directly by Prep-HPLC to afford the title compound (51.8 mg,42%) as a light yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ 9.50 (s, 1H),9.25 (s, 1H), 8.70 (d, J=7.8 Hz, 1H), 8.15 (s, 1H), 7.99-7.94 (m, 2H),7.77-7.71 (m, 1H), 7.21-7.15 (m, 2H), 4.82-4.64 (m, 2H), 4.00 (dd,J=67.5, 9.6 Hz, 2H), 3.57-3.52 (m, 1H), 3.38-3.29 (m, 4H), 2.48-2.41 (m,1H), 2.23-2.19 (m, 1H), 2.05-1.98 (m, 2H).

Example 31 Preparation of(S)-2-(difluoromethyl)-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of methyl(2R)-1-[(4-fluorobenzene)sulfonyl]-2-formylpyrrolidine-2-carboxylate.

A mixture of methyl(2R)-1-[(4-fluorobenzene)sulfonyl]-2-(hydroxymethyl)pyrrolidine-2-carboxylate(100 mg, 0.32 mmol), dichloromethane (20 mL), silica gel (1 g), PCC (136mg, 0.63 mmol) was stirred overnight at room temperature. The mixturewas concentrated, purified by flash chromatography on a silica geleluting with EtOAc/petroleum ether (1/5) to afford the title compound(70 mg, 70%) as colorless oil.

Step 2: Preparation of methyl(2S)-2-(difluoromethyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylate.

A mixture of methyl(2R)-1-[(4-fluorobenzene)sulfonyl]-2-formylpyrrolidine-2-carboxylate(120 mg, 0.38 mmol), dichloromethane (20 mL), DAST (123 mg, 2.00 equiv)was stirred overnight at room temperature. The mixture was concentratedand the residue was purified by flash chromatography on silica geleluting with EtOAc/petroleum ether (1/5) to afford the title compound(90 mg, 70%) as a white solid.

Step 3: Preparation of(2S)-2-(difluoromethyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid.

A mixture of methyl(2S)-2-(difluoromethyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylate(90 mg, 0.27 mmol), methanol (10 mL) and LiOH (20 mg, 0.83 mmol) wasstirred overnight at room temperature. The mixture was concentrated,diluted with water (20 mL), extracted with ether (30 mL). The aqueouslayers was acidified with 3N HCl to pH ˜2-3, extracted with EtOAc (3×30mL). The organic phases were dried over anhydrous Na2SO4 andconcentrated to afford the title compound (30 mg) as colorless oil,which was used in the next step without any further purification.

Step 4: Preparation of(S)-2-(difluoromethyl)-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S)-2-(difluoromethyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (110 mg, 0.34 mmol), HOBt (55 mg, 0.41 mmol), DIPEA (2 mL, 12.10mmol), N,N-dimethylformamide (10 mL), EDC.HCl (78 mg, 0.41 mmol) and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanamine (95 mg,0.37 mmol) was stirred overnight at room temperature. The mixture wasdiluted with EtOAc (100 mL), washed with brine (3×20 mL), dried overNa₂SO₄ and concentrated. The residue was purified by Prep-HPLC to affordthe title compound (12.3 mg) as a light yellow solid. ¹H-NMR (300 MHz,CDCl₃) δ 9.47 (d, J=1.8 Hz, 1H), 9.26 (d, J=1.2 Hz, 1H), 8.66 (dd,J=1.5, 8.1 Hz, 1H), 8.07 (s, 1H), 7.95-7.90 (m, 2H), 7.79 (d, J=8.1 Hz,1H), 7.25-7.20 (m, 2H), 6.61 (t, J=56.1 Hz, 1H), 4.93-4.85 (m, 1H),4.64-4.57 (m, 1H), 3.77-3.71 (m, 1H), 3.29-3.21 (m, 1H), 2.56-2.48 (m,1H), 2.36-227 (m, 1H), 2.10-2.01 (m, 2H).

Example 32 Preparation of(R)-2-cyano-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of(2R)-1-[(4-fluorobenzene)sulfonyl]-2-[(1E)-(hydroxyimino)methyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

A mixture of(2R)-1-[(4-fluorobenzene)sulfonyl]-2-formyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(60 mg, 0.11 mmol), ethanol (10 mL), NH₂OH.HCl (23 mg, 0.33 mmol) andNaOAc (46 mg, 5.00 equiv) was stirred overnight at room temperature. Themixture was concentrated, diluted with EtOAc (100 mL), washed with brine(30 mL), dried over anhydrous Na₂SO₄ and concentrated to afford thetitle compound (70 mg) as a brown solid, which was used in the next stepwithout any further purification.

Step 2: Preparation of(R)-2-cyano-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of Ph₃PO (4 mg, 0.01 mmol), chloroform (15 mL), thionylchloride (45 mg, 0.38 mmol) was stirred for 5 min at 0° C. To this wasadded a solution of(2R)-1-[(4-fluorobenzene)sulfonyl]-2-[(1E)-(hydroxyimino)methyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(70 mg, 0.13 mmol) in chloroform (5 mL) dropwise with stirring at 0° C.The resulting solution was stirred for an additional 30 min at roomtemperature, quenched with saturated NaHCO₃ (20 mL), extracted withEtOAc (3×30 mL) and separated. The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedby Prep-HPLC to afford the title compound (19.6 mg) as a whitesolid.¹H-NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 9.28 (d, J=0.8 Hz, 1H),8.65 (dd, J=6.4, 2.0 Hz, 1H), 8.06-8.03 (m, 3H), 7.78 (d, J=8.4 Hz, 1H),7.48 (t, J=5.4Hz, 1H), 7.27-7.22 (m, 3H), 4.79 (d, J=5.6 Hz, 2H),3.69-3.66 (m, 1H), 3.39-3.35 (m, 1H), 2.68-2.64 (m, 2H), 2.28-2.08(m,2H).

Example 33 Preparation of(1R,3S,4S)-2-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid and (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, andExample 2, steps 2 and 3 (71 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ 9.23 (d,J=1.3 Hz, 1H), 8.78 (t, J=5.9 Hz, 1H), 8.38-8.32 (m, 2H), 8.06-7.99 (m,3H), 7.84 (d, J=8.3 Hz, 2H), 7.46-7.38 (m, 2H), 4.46 (d, J=6.1 Hz, 2H),4.07 (s, 1H), 3.92 (s, 1H), 2.64 (d, J=4.1 Hz, 1H), 2.10 (d, J=9.7 Hz,1H), 1.69-1.59 (m, 1H), 1.52-1.39 (m, 2H), 1.34 (d, J=9.9 Hz, 1H),1.19-1.08 (m, 1H).

Example 34 Preparation of(1R,3S,4S)-2-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide.

The title compound was prepared by the procedures described in Example2, step 1 using(1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid, and Example 2, steps 2 and 3 (72 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ9.43 (d, J=2.1 Hz, 1H), 9.28 (d, J=1.3 Hz, 1H), 8.81 (t, J=5.9 Hz, 1H),8.77-8.72 (m, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.07-7.99 (m, 3H), 7.46-7.39(m, 2H), 4.48 (d, J=6.0 Hz, 2H), 4.07 (s, 1H), 3.92 (s, 1H), 2.65 (d,J=4.0 Hz, 1H), 2.10 (d, J=10.4 Hz, 1H), 1.70-1.57 (m, 1H), 1.47-1.38 (m,2H), 1.34 (d, J=10.1 Hz, 1H), 1.17-1.07 (m, 1H).

Example 35 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl(2S,3R)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(200 mg, 0.86 mmol, 1.00 equiv), DMF (10 mL), HATU (493.6 mg, 1.30 mmol,1.50 equiv), DIEA (446.9 mg, 3.46 mmol, 4.00 equiv), and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (302.3 mg, 1.04 mmol, 1.20 equiv) was stirred for 3 h atroom temperature. The reaction was quenched by addition of 15 mL ofwater and extracted with ethyl acetate (3×15 mL). The organic layerswere combined, washed with water (2×25 mL) and brine (20 mL), dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin 400 mg (99%) of the title compound as orange oil.

Step 2: Preparation of tert-butyl(2R,3S)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

DAST (204 mg, 0.89 mmol, 3.00 equiv) was added dropwise into a solutionoftert-butyl(2S,3R)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate (200 mg, 0.43 mmol, 1.00 equiv) in 10 mL of DCM at 0° C.The resulting solution was stirred for an additional 30 min at roomtemperature, quenched by water (15 mL), and extracted with ethyl acetate(3×15 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, and concentrated. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (40:1) to afford the title compound(85 mg, 42%) as an orange solid.

Step 3: Preparation of(2R,3S)-3-fluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride.

A mixture of tert-butyl(2R,3S)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(85 mg, 0.18 mmol, 1.00 equiv) and HCl in dioxane (10 mL, 1 mol/L) wasstirred for 3 h at room temperature. The resulting solution was dilutedwith 5 mL of EtOAc. The solids were collected by filtration to affordthe title compound (70 mg, 95%) as an orange solid.

Step 4: Preparation of(2R,3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

A mixture of(2R,3S)-3-fluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (70 mg, 0.17 mmol, 1.00 equiv), TEA (51.5 mg, 0.51 mmol,3.00 equiv), 4-fluorobenzene-1-sulfonyl chloride (39.6 mg, 0.20 mmol,1.10 equiv), and 4-dimethylaminopyridine (2.1 mg, 0.02 mmol, 0.10 equiv)in DCM (3 mL) was stirred for 3 h at room temperature. The reaction wasquenched by water (10 mL) and extracted with ethyl acetate (3×10 mL).The organic layers were combined, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1) to afford the titlecompound (40 mg, 44%) as a light yellow solid.¹H-NMR (400 MHz, CDCl₃) δ9.49 (s, 1H), 9.28 (s, 1H), 8.69 (d, J=8.4 Hz, 1H), 7.99 (s, 1H),7.94-7.91 (m, 2H), 7.84-7.80 (m, 2H), 7.29 (t, J=8.4 Hz, 2H), 5.32 (d,J=48 Hz, 1H), 4.96-4.90 (m, 1H), 4.59-4.53 (m, 1H), 4.41 (d, J=22.4 Hz,1H), 3.84 (t, J=8.8 Hz 1H), 3.34-3.27 (m, 1H), 2.26-2.03 (m, 2H).

Example 36 Preparation of(2R,3R)-3-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl(2S,3S)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

A mixture of(2S,3S)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(200 mg, 0.86 mmol, 1.00 equiv), DMF (10 mL), HATU (493.6 mg, 1.30 mmol,1.50 equiv), DIEA (446.9 mg, 3.46 mmol, 4.00 equiv), and[6[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (302.3 mg, 1.04 mmol, 1.20 equiv) was stirred for 3 h atroom temperature. The mixture was quenched by water (15 mL) andextracted with ethyl acetate (3×15 mL). The organic layers werecombined, washed with water (2×25 mL) and brine (20 mL), dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin 400 mg (99%) of the title compound as an orange oil.

Step 2: Preparation of(2R,3R)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

DAST (413.7 mg, 1.81 mmol, 3.00 equiv) was added dropwise into asolution of tert-butyl(2S,3S)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(400 mg, 0.86 mmol, 1.00 equiv) in DCM (15 mL) at −78° C. The resultingsolution was warmed slowly to room temperature, quenched by water (20mL), and extracted with ethyl acetate (3×25 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1) to afford the title compound (210 mg, 52%)as a colorless solid.

Step 3: Preparation of(2R,3R)-3-fluoro-N-([6-[4-(trifluoromethyl)-1lambda4,3-fluorazin-1-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride.

A mixture of tert-butyl(2R,3R)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(200 mg, 0.43 mmol, 1.00 equiv) and HCl in dioxane (10 mL, lmol/L) wasstirred for 5 h at room temperature. The resulting solution was dilutedwith 10 mL of EA. The solids were collected by filtration to afford thetitle compound (105 mg, 60%) as a colorless solid.

Step 4: Preparation of(2R,3R)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

A mixture of(2R,3R)-3-fluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (100 mg, 0.25 mmol, 1.00 equiv), TEA (101 mg, 1.00 mmol,4.00 equiv), 4-fluorobenzene-1-sulfonyl chloride (58.3 mg, 0.30 mmol,1.20 equiv), and 4-dimethylaminopyridine (3 mg, 0.02 mmol, 0.10 equiv)in dichloromethane (10 mL) was stirred for 3 h at room temperature. Themixture was quenched by water (10 mL) and extracted with DCM (3×10 mL).The organic layers were combined, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1) to afford the titlecompound (35 mg, 27%) as a light yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ9.34 (s, 1H), 9.26 (s, 1H), 8.70 (d, J=7.6 Hz, 1H), 8.10 (s, 1H),7.96-7.93 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.31 (t, J=8Hz, 2H), 5.46 (d, J=52 Hz, 1H), 4.95-4.91 (m, 1H), 4.75-4.66 (m, 1H),4.29-4.22 (m, 1H), 3.83 (d, J=8.8 Hz, 2H), 2.32-2.12 (m, 1H), 1.37-1.16(m, 1H).

Example 37 Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2-chloro-5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridine.

A mixture of 2-chloro-5-fluoro-4-iodopyridine (1.5 g, 5.83 mmol),4-(trifluoromethyl)piperidine (890 mg, 5.81 mmol), Pd₂(dba)₃.CHCl₃ (300mg, 0.29 mmol), BINAP (360 mg, 0.58 mmol), and t-BuONa (1.4 g, 14.57mmol) in toluene (15 mL) was irradiated with microwave radiation for 1 hat 125° C. under nitrogen. The reaction was quenched by water (50 mL),extracted with dichloromethane (3×100 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel with ethylacetate/petroleum ether (1:5) to afford the title compound (960 mg, 55%)as a yellow solid.

Step 2: Preparation of5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)picolinonitrile.

A mixture of2-chloro-5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine (400 mg,1.42 mmol), Pd₂(dba)₃.CHCl₃ (72 mg, 0.07 mmol), Zn(CN)₂ (100 mg, 0.85mmol), dppf (80 mg, 0.14 mmol), and Zn (8 mg, 0.12 mmol) in DMA (10 mL)was irradiated with microwave radiation for 1 h at 125° C. undernitrogen. The reaction was quenched by water (100 mL), extracted withdichloromethane (3×150 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel with ethyl acetate/petroleum ether (1:5) toafford the title compound (350 mg, 90%) as a yellow solid.

Step 3: Preparation of(5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methanamine.

A mixture of5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine-2-carbonitrile(200 mg, 0.73 mmol), 10% Pd/C (50 mg), and saturated HCl (0.25 mL) inmethanol (10 mL) was stirred for 1 h at room temperature under anatmosphere of hydrogen gas. The solids were filtered out and thefiltrate was concentrated under reduced pressure to afford the titlecompound (200 mg) as a brown solid, which was used in the next stepwithout any further purification.

Step 4: Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (315 mg, 1.08 mmol), HATU (410 mg, 1.08 mmol), DIEA (0.8 mL, 4.84mmol), and[5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]methanamine(250 mg, 0.90 mmol) in DMF (4 mL) was stirred overnight at roomtemperature. The resulting mixture was purified by Prep-HPLC with thefollowing conditions: Column, X Bridge C18; mobile phase A: water/0.05%NH₄HCO₃; mobile phase B: ACN=30% increasing to ACN=70% within 10 min;detector, UV 254 nm. This resulted in the title compound (28.2 mg) as awhite solid.¹H-NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 8.03-7.99 (m, 2H),7.39-7.34 (m, 2H), 7.17 (d, J=7.6 Hz, 2H), 5.14 (d, J=52.4 Hz, 1H), 4.47(s, 2H), 4.28-4.24 (m, 1H), 4.03 (d, J=12.8 Hz, 2H), 3.83-3.70 (m, 2H),2.97 (t, J=12.8 Hz, 2H), 2.51-2.40 (m, 2H), 2.25-2.12 (m, 1H), 1.93 (d,J=12.8 Hz, 2H), 1.71-1.65 (m, 2H).

Table 3: IC₅₀ Determinations of Exemplified Compounds.

IC₅₀s (effective concentration) of compounds on the human TRPA1 channelwere determined using a Hamamatsu FDSS fluorescence plate reader. CHOcells expressing human TRPA1 were plated into 384-well plates, incubatedovernight at 37C, and loaded with BD calcium indicator dye for 1 hr at37° C. followed by 15 minutes. at room temperature. The assay buffer wasHank's Balanced Salt Solution (HBSS) containing 20 mM HEPES (pHreadjusted to 7.4) along with 0.02% BSA.

Following dye load and plate cool down, compounds were added to thecells using the FDSS while monitoring fluorescence to determine whetherany of the test compounds have TRPA1 agonist activity. Plates were thenincubated with compound for 20 minutes at room temperature prior toadding agonist. Following this incubation, 100 mM cinnamaldehyde wasadded to all wells of the plate and block of this cinnamaldehyde inducedcalcium influx was measured.

IC₅₀s were fit with a standard Hill function, keeping the Hillcoefficient (n) fixed to 1.5. Fixing the Hill coefficient will generallyreduce variability of the IC₅₀ determination. The IC₅₀s were examined byeye to make sure the MIN and MAX points were set correctly prior tovalidation of the results. Data for representative compounds of formulaI is provided in Table 3 below.

TABLE 3 IC₅₀ Determinations of Exemplified Compounds. hTRPA1 AUC ExampleIC₅₀ Number Structure (μM)  1

0.051  2

0.059  4

0.819  3

0.097  5

0.015  6

0.023 14

0.268  7

0.284  9

0.020  8

0.017 17

0.055 15

0.030 16

0.008 18

0.049 19

0.016 10

0.107 11

0.434 20

0.007 21

0.021 22

0.087 23

2.7 24

0.027 25

0.126 26

0.030 27

3.0 28

0.229 29

0.032 12

0.030 13

0.308 13

0.029 30

0.252 31

0.029 32

0.867 35

0.023 33

0.023 34

0.040 36

0.120 37

0.021

Example 38 Preparation of(2R,3S)-N-([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 5-bromo-2,3-dihydro-1H-isoindol-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (3 g, 9.74 mmol, 1.0equiv) and ammonium hydroxide (30 mL, 30%) in 1,4-dioxane (250 mL) wasstirred for 3 h at 20° C. The resulting mixture was concentrated undervacuum. The crude product was purified by re-crystallization from ethylacetate to afford the title compound (1.8, 87%) as a white solid.

Step 2: Preparation of tert-butyl5-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

A mixture of 5-bromo-2,3-dihydro-1H-isoindol-1-one (1.38 g, 6.51 mmol,1.0 equiv), TEA (1.8 g, 17.79 mmol, 2.70 equiv), 4-dimethylaminopyridine(73 mg, 0.60 mmol) and di-tert-butyl dicarbonate (2.6 g, 11.91 mmol,1.80 equiv) in tetrahydrofuran (50 mL) was stirred for 12 h at 20° C.The resulting mixture was concentrated under vacuum. The residue wasdissolved in ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1/10)to afford the title compound (1.7 g, 84%) as a white solid.

Step 3: Preparation of 5-bromo-2,3-dihydro-1H-isoindol-1-one

A mixture of tert-butyl5-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (1.7 g, 5.45 mmol,1.00 equiv), KOAc (1.6 g, 16.30 mmol, 3.00 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.08 g, 8.19 mmol, 1.50 equiv), and Pd(dppf)Cl₂ (395 mg, 0.54 mmol,0.10 equiv) in 1,4-dioxane (40 mL) was stirred for 12 h at 90° C. undernitrogen. The resulting mixture was concentrated under vacuum. Theresidue was dissolved in ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (2 g, crude) as a white solid.

Step 4: Preparation of tert-butyl1-oxo-5-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydro-1H-isoindole-2-carboxylate

A mixture of tert-butyl 1-oxo-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole-2-carboxylate(500 mg, 1.39 mmol, 1.00 equiv), potassium carbonate (575 mg, 4.16 mmol,3.00 equiv), 5-bromo-2-(trifluoromethyl)pyrimidine (313 mg, 1.38 mmol,1.00 equiv), and Pd(dppf)Cl₂ (106 mg, 0.14 mmol, 0.10 equiv) in dioxane(13 mL)/water(1.3 mL) was stirred for 12 h at 80° C. under nitrogen. Thereaction mixture was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/10) to afford the title compound (400 mg,76%) as an off-white solid.

Step 5: Preparation of2-([[(tert-butoxy)carbonyl]amino]methyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoicacid

A mixture of tert-butyl1-oxo-5-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydro-1H-isoindole-2-carboxylate(250 mg, 0.66 mmol, 1.00 equiv) and LiOH (100 mg, 4.18 mmol, 6.30 equiv)in tetrahydrofuran (3 mL)/water (0.3 mL) was stirred for 12 h at 20° C.The resulting solution was diluted with water and extracted with diethylether. The pH value of the aqueous solution was adjusted to 3-4 with 5%HCl. The resulting solution was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (180 mg, 69%) as a brown solid.

Step 6: Preparation of tert-butylN-([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamate

A mixture of2-([[(tert-butoxy)carbonyl]amino]methyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoicacid (160 mg, 0.40 mmol, 1.00 equiv), DIEA (600 mg, 4.64 mmol, 11.50equiv), HATU (183 mg, 0.48 mmol, 1.20 equiv), and NH₄Cl (260 mg, 4.86mmol, 12.10 equiv) in DMF (5 mL) was stirred for 12 h at 20° C. Theresulting solution was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/1) to afford the title compound (160 mg,100%) as a brown solid.

Step 7: Preparation of2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamidehydrochloride

A mixture of tert-butylN-([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamate(160 mg, 0.40 mmol, 1.00 equiv) and HCl (saturated solution in 20 mL of1,4-dioxane) was stirred for 2 h at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (120mg, crude) as a white solid.

Step 8: Preparation of tert-butyl(2S,3R)-2-[([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(93.67 mg, 0.41 mmol, 1.00 equiv), DIEA (157.06 mg, 1.22 mmol, 3.00equiv), HATU (231.03 mg, 0.61 mmol, 1.50 equiv), and2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamidehydrochloride (120.00 mg, 0.41 mmol, 1.00 equiv) in DMF (5 mL) wasstirred for 2 h at room temperature. The resulting solution was dilutedwith ethyl acetate, washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with dichloromethane/methanol (20:1) to affordthe title compound (130 mg, 63%) as a white solid.

Step 9: Preparation of tert-butyl(2R,3S)-2-[([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate

DAST (174.01 mg, 1.08 mmol, 5.00 equiv) was added dropwise into astirred mixture of tert-butyl(2S,3R)-2-[([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate(110.00 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (5 mL) at −78° C.under nitrogen. The reaction was stirred for 30 min at −78° C. and 12 hat room temperature. The reaction was then quenched by water andextracted with dichloromethane. The combined extracts were washed withsaturated aqueous sodium bicarbonate and brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:1)to afford the title compound (60 mg, 54%) as a white solid.

Step 10: Preparation of tert-butyl(2R,3S)-2-[([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate

TFAA (49.28 mg, 0.23 mmol, 2.00 equiv) was added to a mixture oftert-butyl(2R,3S)-2-[([2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate (60.00 mg, 0.12 mmol, 1.00 equiv) in dichloromethane (5mL)/triethylamine (11.87 mg, 0.12 mmol, 1.00 equiv). The reaction wasstirred for 10 min at room temperature, quenched by water, and extractedwith dichloromethane. The combined extracts were washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:5) to afford the title compound (50 mg, 86%)as a white solid.

Step 11: Preparation of(2R,3S)-N-([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)-3-fluoropyrrolidine-2-carboxamide

A mixture of tert-butyl(2R,3S)-2-[([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate(50 mg, 0.10 mmol, 1.00 equiv) and HCl (saturated solution in 5 mL of1,4-dioxane) was stirred for 3 h at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (40mg, crude) as a white solid.

Step 12: Preparation of(2R,3S)-N-([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2R,3S)-N-([2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl)-3-fluoropyrrolidine-2-carboxamide(47.00 mg, 0.119 mmol, 1.000 equiv), triethylamine (36.27 mg, 0.358mmol, 3.000 equiv), and 4-fluorobenzene-1-sulfonyl chloride (46.51 mg,0.239 mmol, 2.000 equiv) in dichloromethane (5 ml) was stirred for 12 hat room temperature. The reaction was then quenched by water andextracted with dichloromethane. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:1). The crude product (40 mg) wasre-purified by Prep-HPLC to afford the title compound (25.1 mg, 38%) asa white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.40 (s, 1H), 8.10 (s, 1H), 8.03-7.91 (m, 4H),7.41-7.35 (m, 2H), 5.19 (d, J=52 Hz, 1H), 4.92-4.87 (m, 1H), 4.64 (d,J=24.4 Hz, 2H), 4.36 (d, J=24.4 Hz, 1H), 3.80-3.85 (m, 1H), 3.33-3.27(m, 1H), 2.29-2.14 (m, 2H).

Example 39 Preparation of(2S,5R)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-butyl 2-methyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate

Lithium triethylborohydride (34.5 mL, 1.20 equiv) was added dropwiseinto a solution of 1-tert-butyl 2-methyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (7 g, 1.00 equiv) intetrahydrofuran (30 mL) at −78° C. under nitrogen. The reaction wasstirred for 2 h at −78° C. and quenched by aqueous sodium bicarbonate at0° C. 30% H₂O₂ (15 mL) was added and the reaction was stirred for 20minutes. The mixture was extracted with Et₂O (2×50 mL), washed withbrine, dried over Na₂SO₄, and concentrated under vacuum. To theresulting crude aminol in methanol (25 mL) was added PTSA (656 mg, 0.38mmol, 0.12 equiv). The resulting solution was stirred for 12 h at roomtemperature, quenched by aqueous sodium bicarbonate, extracted withether, washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3). This resultedin the title compound (4.1 g) as light yellow oil.

Step 2: Preparation of 1-tert-butyl 2-methyl(2S)-5-methylpyrrolidine-1,2-dicarboxylate

A mixture of copper(I) bromide-dimethyl sulfide (1.05 g, 5.11 mmol, 4.00equiv) and diethyl ether (13 mL) was added MeMgBr (1.645 mL, 3M in Et₂O)dropwise at −40° C. under nitrogen. After 45 min at −40° C. the mixturewas cooled to −78° C. and BF₃.Et₂O (0.62 mL, 5.24 mmol, 4.00 equiv) wasadded dropwise at −78° C. The reaction was stirred for 30 min and1-tert-butyl 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (320mg, 1.23 mmol, 1.00 equiv) in diethyl ether (17 mL) was added at −78° C.The resulting solution was stirred for 30 min at −78° C. and lh at roomtemperature. The reaction mixture was then stirred with aqueous NH₄Clfor 1 h at room temperature. The resulting solution was extracted withEt₂O, washed with sodium bicarbonate and brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:4).This resulted in the title compound (180 mg, 60%) as colorless oil.

Step 3: Preparation of(2S)-1-[(tert-butoxy)carbonyl]-5-methylpyrrolidine-2-carboxylic acid

A mixture of 1-tert-butyl 2-methyl(2S)-5-methylpyrrolidine-1,2-dicarboxylate (180 mg, 0.74 mmol, 1.00equiv) and LiOH (1.6 mg, 0.07 mmol, 0.10 equiv) in methanol (2 mL)/water(0.2 mL) was stirred overnight at room temperature and concentratedunder vacuum. The residue was diluted with 10 mL of water and the pHvalue of the solution was adjusted to 3 with diluted HCl. The resultingsolution was extracted with dichloromethane, dried over sodium sulfate,and concentrated under vacuum. This resulted in the title compound (110mg, 65%) as light yellow oil.

Step 4: Preparation of tert-butyl(2R,5S)-2-methyl-5-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,5R)-1-[(tert-butoxy)carbonyl]-5-methylpyrrolidine-2-carboxylic acid(120 mg, 0.52 mmol, 1.00 equiv), HATU (298 mg, 0.78 mmol, 1.50 equiv),DIEA (202 mg, 1.56 mmol, 3.00 equiv), and6[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-ylmethanamine (182 mg,0.72 mmol, 1.20 equiv) in DMF (5 mL) was stirred overnight at roomtemperature. The reaction solution was diluted with 40 mL of ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1) to afford thetitle compound (90 mg, 37%) as light yellow oil.

Step 5: Preparation of(2S,5R)-5-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2R,5S)-2-methyl-5-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(90 mg, 0.19 mmol, 1.00 equiv) and saturated HCl in 1,4-dioxane (10 mL)was stirred overnight at room temperature and concentrated under vacuum.This resulted in the title compound (85 mg) as light yellow oil.

Step 6: Preparation of(2S,5R)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A solution of(2S,5R)-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (75 mg, 0.19 mmol, 1.0 equiv), TEA (56.6 mg, 0.56 mmol,3.000 equiv), 4-dimethylaminopyridine (2.28 mg, 0.019 mmol, 0.1 equiv),and 4-fluorobenzene-1-sulfonyl chloride (43.5 mg, 0.224 mmol, 1.2 equiv)in dichloromethane (5 mL) was stirred for 1.5 h at room temperature. Theresulting mixture was diluted with DCM, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC to afford the title compound (2 lmg,21%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.49 (s, 1H), 9.26 (s, 1H), 8.68-8.65 (d,J=8.4 Hz, 1H), 8.15 (s, 1H), 7.97-7.93 (m, 2H), 7.77-7.16 (m, 1H),7.26-7.16 (m, 3H), 4.94-4.82 (m, 1H), 4.65-4.57 (m, 1H), 4.43-4.41 (m,1H), 4.28-4.24 (m, 1H), 2.29-2.15 (m, 3H), 1.65-1.59 (m, 1H), 1.14-1.12(m, 3H).

Example 40: Preparation of(2S,4S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-4-(fluoromethyl)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-butyl 2-methyl4-hydroxy-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl4-methylidenepyrrolidine-1,2-dicarboxylate (1 g, 4.14 mmol, 1.00 equiv)and 4-methylmorpholin-4-ium-4-olate (1.175 g, 10.03 mmol, 1.60 equiv) inacetone (10 mL)/water(10 mL) was stirred for 7 h at room temperature.The mixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:1) toafford the title compound (700 mg, 61%) as orange oil.

Step 2: Preparation of 1-tert-butyl 2-methyl4-[[(tert-butyldimethylsilyl)oxy]methyl]-4-hydroxypyrrolidine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl4-hydroxy-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (1.068 g, 3.88mmol, 1.00 equiv), TBS-Cl (1.165 g, 7.73 mmol, 2.00 equiv), imidazole(528 mg, 7.76 mmol, 2.00 equiv), and 4-dimethylaminopyridine (47 mg,0.38 mmol, 0.10 equiv) in N ,N-dimethylformamide (27 mL) was stirred for12 h at room temperature. The mixture was diluted with water andextracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:10). This resulted in the titlecompound (1.37 g, 91%) as light yellow oil.

Step 3: Preparation of 1-tert-butyl 2-methyl(2S)-4-[[(tert-butyldimethylsilyl)oxy]methyl]-4-fluoropyrrolidine-1,2-dicarboxylate

DAST (1.13 g, 7.01 mmol, 2.00 equiv) was added dropwise into a solutionof 1-tert-butyl 2-methyl(2S)-4-[[(tert-butyldimethylsilyl)oxy]methyl]-4-hydroxypyrrolidine-1,2-dicarboxylate(1.37 g, 3.52 mmol, 1.00 equiv) in dichloromethane (25 mL) at −78° C.under nitrogen. The resulting solution was stirred for 1.5 h at roomtemperature. The reaction was then quenched by water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (1.25g, 91%) as light yellow oil.

Step 4: Preparation of 1-tert-butyl 2-methyl(2S)-4-fluoro-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl(2S)-4-[[(tert-butyldimethylsilyl)oxy]methyl]-4-fluoropyrrolidine-1,2-dicarboxylate(1 g, 2.55 mmol, 1.00 equiv), TBAF (1.335 g, 5.11 mmol, 2.00 equiv) intetrahydrofuran (5 mL) was stirred for 12 h at room temperature. Themixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:10) toafford the title compound (520 mg, 73%) as colorless oil.

Step 5: Preparation of 1-tert-butyl 2-methyl(2S)-4-fluoro-4-(fluoromethyl)pyrrolidine-1,2-dicarboxylate

BAST (1.637 g, 7.40 mmol, 4.00 equiv) was added dropwise into a solutionof 1-tert-butyl 2-methyl(2S)-4-fluoro-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (513 mg,1.85 mmol, 1.00 equiv) in chloroform (10 mL) at 0° C. under nitrogen.The resulting solution was stirred for 5 h at 60° C. The reactionmixture was cooled to room temperature, quenched by water, and extractedwith dichloromethane. The combined extracts were washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:10). This resulted in the title compound (300mg, 58%) as orange oil.

Step 6: Preparation of(2S)-1-[(tert-butoxy)carbonyl]-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxylicacid

A mixture of 1-tert-butyl 2-methyl(2S)-4-fluoro-4-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (270 mg,0.97 mmol, 1.00 equiv) and LiOH (116 mg, 4.84 mmol, 5.00 equiv) intetrahydrofuran (3 mL)/water (2 mL) was stirred for 5 h at roomtemperature. The resulting solution was diluted with water and extractedwith ethyl acetate. The pH value of the aqueous solution was adjusted to4 with acetic acid. The resulting solution was extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (250 mg,97%) as orange oil.

Step 7: Preparation of tert-butyl(2S)-4-fluoro-4-(fluoromethyl)-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of(2S)-1-[(tert-butoxy)carbonyl]-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxylicacid (110 mg, 0.41 mmol, 1.00 equiv), HATU (173.4 mg, 0.46 mmol, 1.10equiv), DIEA (160.6 mg, 1.24 mmol, 3.00 equiv), and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (120.3 mg, 0.41 mmol, 1.00 equiv) in N,N-dimethylformamide(6 mL) was stirred for 2 h at room temperature. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1) to afford the title compound(170 mg, 82%) as a yellow solid.

Step 8: Preparation of(2S)-4-fluoro-4-(fluoromethyl)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S)-4-fluoro-4-(fluoromethyl)-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(170 mg, 0.34 mmol, 1.00 equiv) and saturated hydrogen chloride indioxane (5 mL) was stirred for 20 h at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (125mg, 84%) as a pink solid.

Step 9: Preparation of(2S,4S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-4-(fluoromethyl)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of 4-fluorobenzene-1-sulfonyl chloride (125 mg, 0.642 mmol,1.00 equiv), TEA (86.6 mg, 0.856 mmol, 3.00 equiv), and(2S)-4-fluoro-4-(fluoromethyl)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (61.0 mg, 0.139 mmol, 1.10 equiv) in dichloromethane (5mL) was stirred for 3 h at room temperature. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1). The crude product was purifiedby Prep-HPLC to afford the title compound (15.2 mg, 4%) as a whitesolid. t_(R)=0.93 min (CHIRALPAK AS-3, 4.6×100 cm, 3 μm, MeOH (0.1%DEA)=10% to 40% in 2.0 min, hold 1.0 min at 40%, 4 ml/min).

¹H NMR (400 MHz, CDCl₃) δ 9.51 (s, 1H), 9.29 (s, 1H), 8.70-8.68 (d, J=8Hz, 1H), 8.09 (s, 1H), 7.95-7.92 (m, 2H), 7.83-7.81 (d, J=8 Hz, 1H),7.61 (s, 1H), 7.52-7.28 (m, 2H), 4.97-4.91 (m, 1H), 4.61-4.35 (m, 4H),3.93-3.71 (m, 2H), 2.52-2.49 (m, 1H), 2.38-2.27 (m, 1H).

And(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-4-(fluoromethyl)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidewas also isolated (31.8 mg, 9%) as a white solid. t_(R)=1.18 min(CHIRALPAK AS-3, 4.6×100 cm, 3 μm, MeOH (0.1% DEA)=10% to 40% in 2.0min, hold 1.0 min at 40%, 4 ml/min).

¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 1H), 9.27 (s, 1H), 8.68-8.66 (d, J=8Hz, 1H), 8.00 (s, 1H), 7.96-7.92 (m, 2H), 7.82-7.80 (d, J=8 Hz, 1H),7.69 (s, 1H), 7.35-7.31 (m, 2H), 4.92-4.85 (m, 1H), 4.70-4.64 (m, 1H),4.59-4.31 (m, 3H), 4.02-3.94 (m, 1H), 3.45-3.33 (m, 1H), 2.65-2.57 (m,1H), 2.03-1.72 (m, 1H).

The 4-proline stereochemistry for the above two compounds wasarbitrarily assigned. The 2-proline stereochemistry for the above twocompounds is as shown.

Example 41 Preparation of(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-5-oxohexanoate

A solution of MeMgBr (1M) (33 mL, 1.00 equiv) was added dropwise to asolution of 1-tert-butyl 2-methyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (8 g, 32.89 mmol, 1.00 equiv) intetrahydrofuran (20 mL) at −40° C. The resulting solution was stirredfor 2 h at −40° C. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by saturated NH₄Cl. Theresulting solution was extracted with ethyl acetate and dried overanhydrous sodium sulfate. The solids were filtered off. The filtrate wasconcentrated under reduced pressure. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:5) toafford the title compound (5.1 g, 60%) as light yellow oil.

Step 2: Preparation of methyl(2S)-5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate

A solution of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-5-oxohexanoate (3.7 g, 14.27 mmol,1.00 equiv) and trifluoroacetic acid (10 mL, 134.63 mmol, 1.00 equiv) indichloromethane (20 mL) was stirred for 1 day at room temperature. Theresulting mixture was concentrated under vacuum to afford the titlecompound (3.5 g) as light yellow oil.

Step 3: Preparation of methyl (2S,5S)-5-methylpyrrolidine-2-carboxylate

A mixture of methyl (2S)-5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate(350 mg, 2.48 mmol, 1.00 equiv) and palladium on carbon (300 mg) inmethanol (3 mL) was stirred for 8 h at room temperature under hydrogen.The solids were filtered out. The filtrate was concentrated under vacuumto afford the title compound (400 mg) as light yellow oil.

Step 4: Preparation of methyl(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methylpyrrolidine-2-carboxylate

A mixture of methyl (2S,5S)-5-methylpyrrolidine-2-carboxylate (350 mg,2.44 mmol, 1.00 equiv), TEA (987 mg, 9.75 mmol, 4.00 equiv),4-dimethylaminopyridine (28 mg, 0.23 mmol, 0.10 equiv), and4-fluorobenzene-1-sulfonyl chloride (567 mg, 2.91 mmol, 1.20 equiv) indichloromethane (30 mL) was stirred for 8 h at room temperature. Theresulting solution was diluted with ethyl acetate, washed with brine,and dried over anhydrous sodium sulfate. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:3) toafford the title compound (190 mg, 26%) as light yellow oil.

Step 5: Preparation of(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methylpyrrolidine-2-carboxylicacid

A mixture of methyl(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methylpyrrolidine-2-carboxylate(160 mg, 0.53 mmol, 1.00 equiv) and LiOH (25.5 mg, 1.06 mmol, 1.00equiv) in methanol (4 mL)/water(0.5 mL) was stirred overnight at roomtemperature. The resulting solution was diluted with 20 mL of water. ThepH value of the solution was adjusted to 9 with Na₂CO₃. The resultingsolution was extracted with dichloromethane, dried over anhydrous sodiumsulfate, and concentrated under vacuum. This resulted in the titlecompound (180 mg) as a white solid.

Step 6: Preparation of(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methylpyrrolidine-2-carboxylicacid (150 mg, 0.522 mmol, 1.00 equiv), HATU (285 mg, 0.750 mmol, 1.50equiv), DIEA (190 mg, 1.470 mmol, 3.000 equiv), and6[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-ylmethanaminehydrochloride (182 mg, 0.626 mmol, 1.200 equiv) in N,N-dimethylformamide(4 mL) was stirred for 1 h at room temperature. The resulting solutionwas diluted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby Prep-HPLC to afford the title compound (99.7 mg, 36%) as a whitesolid.

¹FINMR (300 MHz, CDCl₃) δ 9.49 (s, 1H), 9.27 (s, 1H), 8.71-8.70 (d,J=1.5 Hz, 1H), 8.04 (s, 1H), 7.95-7.90 (m, 2H), 7.82-7.80 (m, 1H),7.69-7.67 (m, 1H), 7.31-7.26 (m, 2H), 5.01-4.92 (m, 1H), 4.60-4.53 (m,1H), 4.22-4.17 (m, 1H), 3.73-3.71 (m, 1H), 2.19-2.16 (m, 1H), 1.77-1.68(m, 3H), 1.60-1.51 (m, 3H).

Example 42 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide.

6-chloro-2′-(trifluoromethyl)-4,5′-bipyrimidine

A solution of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (100 mg,0.50 mmol), 4,6-dichloropyrimidine (0.742559 mmol), cesium carbonate(322.595 mg, 0.99 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii)dichloromethane adduct (0.10 equiv., 0.050 mmol) in acetonitrile (6.0ml) and water (3.0 mL) was degassed. The reaction mixture was heated at95° C. for 2 h. The reaction was filtered thru celite. The crude productwas purified by flash chromatography (EtOAc/Hex_eluted at 20% EtOAc) togive 74 mg, 57.3% yield. LCMS (ESI) m/z:260.9 [M+H]+

2′-(trifluoromethyl)[4,5′-bipyrimidine]-6-carbonitrile

A solution of 4-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidine(A, 150 mg, 0.58 mmol), zinc cyanide (82.763 mg, 0.69071 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (48.0 mg, 0.058 mmol) in N,N-dimethylformamide(5.7559 mL, 74.4 mmol) was stirred at 150° C. 45min. The reaction wasquenched with water and extracted with EtOAc. The organic layers wasdried with sodium sulfate, filtered, and concentrated via rotovap. Thecrude product was purified by flash chromatography (MeOH/DCM) to give103 mg, 71.2% yield. LCMS (ESI) m/z:252.0 [M+H]+

(2′-(trifluoromethyl)[4,5′-bipyrimidin]-6-yl)methanamine

A solution of6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidine-4-carbonitrile (A, 140mg, 0.557 mmol) and palladium on Carbon 10% (11.864 mg, 0.0111 mmol) inmethanol (11.148 mL) and hydrochloric acid (0.10 mL, 2.7870 mmol) wasstirred under H2 10min. The reaction was filtered thru celite. The crudeproduct was carried to next step. LCMS (ESI) m/z:255.95 [M+H]+

(2S,4R)-tert-butyl4-fluoro-2-(((2′-(trifluoromethyl)[4,5′-bipyrimidin]-6-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution of(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(125 mg, 0.536 mmol) and[6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methanamine (136.77mg, 0.536 mmol) in N,N-dimethylformamide (2.0 mL) was addedN,N-diisopropylethylamine (0.140 mL, 0.80389 mmol) and HATU (249.52 mg,0.64311 mmol). The reaction mixture was stirred at RT 2 h.The reactionwas quenched with water and extracted with EtOAc. The organic layers wasdried with sodium sulfate, filtered, and concentrated via rotovap. Thecrude product was carried to next step. LCMS (ESI) m/z:471.20 [M+H]+

(2S,4R)-4-fluoro-N-((2′-(trifluoromethyl)[4,5′-bipyrimidin]-6-yl)methyl)pyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-4-fluoro-2-[[6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate(252 mg, 0.5357 mmol) in 1,4-dioxane (2.7 mL) was added hydrochloricacid (4 mol/L) in 1,4-dioxane (1.34 mL, 5.357 mmol). The reactionmixture was stirred at RT 6 h. The reaction was concentrated and carriedto next step. LCMS (ESI) m/z:371.05 [M+H]+

(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-fluoro-N-[[6-[2-(trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide(198 mg, 0.5347 mmol) in dichloromethane (10.71 mL) was addedtriethylamine (1.49 mL, 10.71 mmol) then 4-fluorobenzenesulfonylchloride (156.4 mg, 0.8036 mmol). The reaction was stirred at RT 1 h.The reaction was concentrated and submitted for rHPLC to give 119 mg,42.03% yield.

1H NMR (400 MHz, DMSO) δ 9.72-9.68 (s, 2H), 9.36-9.33 (d, J=1.2 Hz, 1H),9.21-9.11 (t, J=6.0 Hz, 1H), 8.30-8.25 (d, J=1.3 Hz, 1H), 8.08-7.99 (m,2H), 7.52-7.43 (m, 2H), 5.31-5.12 (d, J=52.3 Hz, 1H), 4.61-4.47 (m, 2H),4.30-4.20 (dd, J=10.0, 7.1 Hz, 1H), 3.80-3.58 (m, 2H), 2.46-2.37 (m,1H), 2.25-2.03 (dddd, J=42.7, 13.8, 10.0, 3.3 Hz, 1H)., LCMS (ESI)m/z:529.11 [M+H]+.

Example 43 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-methyl-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

(2S,4R)-tert-butyl4-fluoro-2-(((2-methyl-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S,4R)-2-[[2-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(120 mg, 0.2381 mmol) and trimethylboroxine (45.30 mg, 0.0504 mL, 0.3572mmol) in 1,2-dimethoxyethane (4.763 mL)was added potassium carbonate(99.73 mg, 0.7144 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.60 mg,0.02381 mmol). The reaction mixture was degassed then heated microwaveat 120° C. 40min. The reaction was filtered thru celite concentrated.The crude product was purified by flash chromatography (DCM/MeOH) togive 95 mg, 82.5% yield. LCMS (ESI) m/z:484.15 [M+H]+

(2S,4R)-4-fluoro-N-((2-methyl-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-4-fluoro-2-[[2-methyl-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methylcarbamoyl]pyrrolidine-1-carboxylate(A, 95 mg, 0.1965 mmol) in 1,4-dioxane (0.9824 mL) was addedhydrochloric acid (4 mol/L) in 1,4-dioxane (0.4912 mL, 1.965 mmol). Thereaction mixture was stirred at RT 6 h. The reaction was concentratedand carried to next step. LCMS (ESI) m/z:384.1 [M+H]+

(2S,4R)-4-fluoro-1-(4-fluorophenyl)sultonyl-N-[[2-methyl-6-[2-(tnfluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-fluoro-N-[[2-methyl-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide(75.31 mg, 0.1965 mmol) in dichloromethane (3.930 mL) was addedtriethylamine (0.548 mL, 3.930 mmol) then 4-fluorobenzenesulfonylchloride (57.36 mg, 0.2947 mmol). The reaction was stirred at RT 1 h.The reaction was concentrated and submitted for rHPLC to give 65.4 mg,61.47% yield.

1H NMR (400 MHz, DMSO) δ 9.67-9.58 (s, 2H), 9.04-8.93 (t, J=6.0 Hz, 1H),8.06-7.95 (m, 3H), 7.53-7.42 (m, 2H), 7.41-7.36 (d, J=1.3 Hz, 1H),5.30-5.11 (d, J=52.4 Hz, 1H), 4.55-4.37 (m, 2H), 4.24-4.17 (dd, J=10.0,7.1 Hz, 1H), 3.76-3.58 (m, 2H), 2.61-2.56 (s, 3H), 2.22-2.00 (m, 1H).,LCMS (ESI) m/z:542.13 [M+H]+

Example 44 Preparation of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step1: Preparation of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-[(3-bromo-5-fluorophenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(500 mg, 1.05 mmol, 1.00 equiv), potassium carbonate (430 mg, 3.11 mmol,3.00 equiv), [2-methoxy-6-(trifluoromethyl)pyridin-3-yl]boronic acid(230 mg, 1.04 mmol, 1.00 equiv), and Pd(dppf)Cl₂ (78 mg, 0.11 mmol, 0.10equiv) in 1,4-dioxane (12 mL)/water(1.2 mL) was stirred for 12 h at 80°C. under nitrogen. The resulting solution was diluted with ethylacetate, washed with brine, dried over sodium sulfate, and concentratedunder vacuum. The residue was purified by Prep-HPLC to afford the titlecompound (200 mg, 33%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.88-7.85 (m, 3H),7.85-7.78 (m, 1H), 7.35-7.26(m, 3H), 7.24-7.22 (m, 2H), 7.21-7.07 (d, 1H), 5.10-4.97 (m, 1H),4.67-4.62 (m, 1H), 4.51-4.48 (m, 1H), 4.29-2.25 (m, 1H), 4.03 (s, 3H),3.95-3.86 (m, 1H),3.67-3.42 (s, 1H), 2.52-2.50 (m, 1H), 2.49-2.35 (m,1H).

Example 45 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[6-(trifluoromethyl)pyridazin-3-yl]phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide.

To a microwave vial was added(2S)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-4-methyl-pyrrolidine-2-carboxamide(INT-52-5 of Example 52) (60 m

g, 0.12 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (29 mg, 0.16mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(6.3 mg, 0.0089 mmol), sodium carbonate (17 mg, 0.16 mmol) and potassiumacetate (15 mg, 0.16 mmol). Acetonitrile (0.8 mL) and water (0.16 mL)were added and nitrogen was bubbled through the reaction mixture for 3mins then heated to 140° C. in the microwave for 30 mins. The reactionmixture was diluted with dichloromethane, filtered through celite,eluting with dichloromethane and the filtrate was concentrated in vacuo.The residue was adsorbed onto silica and purified by flash columnchromatography with 0-100% EtOAc in heptane to afford the partiallypurified product. The residue was further purified by RP-HPLC to yieldthe title compound as a white solid (17.0 mg, 27%). MS-ESI: [M+H]⁺559.12

¹H NMR (400 MHz, DMSO) δ 8.92 (t, J=6.1 Hz, 1H), 8.57 (d, J=8.9 Hz, 1H),8.39 (d, J=9.0 Hz, 1H), 8.07 (t, J=1.4 Hz, 1H), 8.04-7.92 (m, 3H),7.51-7.38 (m, 3H), 4.57-4.42 (m, 2H), 4.25-4.16 (m, 1H), 3.72-3.47 (m,2H), 2.49-2.32 (m, 1H), 2.14-1.94 (m, 1H), 1.38 (d, J=20.8 Hz, 3H).

Example 46 Preparation of(2S,4R)-4-fluoro-1-((4-fluorophenyl)sulfonyl)-4-methyl-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: tert-butyl((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)carbamate(INT-46-7)

To a microwave vial was added tert-butylN-[(6-chloropyrimidin-4-yl)methyl]carbamate (150 mg, 0.58 mmol),4-(trifluoromethoxy)phenylboronic acid (174 mg, 0.82 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(33 mg, 0.047 mmol), sodium carbonate (87 mg, 0.82 mmol) and potassiumacetate (81 mg, 0.82 mmol). Acetonitrile (3.0 mL) and water (0.6 mL)were added and nitrogen was bubbled through the reaction mixture for 3mins then heated to 140° C. in the microwave for 30 mins. The reactionmixture was diluted with dichloromethane, filtered through celite,eluting with dichloromethane and the filtrate was concentrated in vacuo.The residue was adsorbed onto silica and purified by flash columnchromatography with 0-100% EtOAc in heptane to afford the desiredcompound as a yellow foam (215 mg, 100%). MS-ESI: [M+H]⁺370.2

Step 2: (S)-benzyl4-oxo-2-(((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(INT-46-8)

To a solution of tert-butylN-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]carbamate (215mg, 0.6038 mmol,) in dichloromethane (6 mL) was added hydrochloric acid(4 mol/L) in 1,4-dioxane (3 mL, 12 mmol) and the reaction mixture wasstirred for 2 h at room temperature then concentrated in vacuo. Theresidue was dissolved in dichloromethane (3 mL) and(2S)-1-benzyloxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (100 mg,0.38 mmol) was added followed by N,N-diisopropylethylamine (147.3 mg,0.199 mL, 1.140 mmol). The reaction mixture was stirred overnight atroom temperature then quenched with sat. aq. sodium bicarbonate andextracted with EtOAc (3×). The combined organic extracts were washedwith brine then dried over sodium sulfate, filtered and concentrated invacuo. The residue was adsorbed onto silica and purified by flash columnchromatography with 0-10% MeOH in DCM to afford the desired compound asa beige solid (142 mg, 46%). MS-ESI: [M+H]⁺515.2

Step 3: (2S)-benzyl4-hydroxy-4-methyl-2-(((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(INT-46-9)

To a solution of benzyl(2,9-4-oxo-2-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate(142 mg, 0.28 mmol) in tetrahydrofuran (3.0 mL) was added lanthanum(III)chloride bis(lithium chloride) complex solution (0.6 M in THF) (0.51 mL,0.30 mmol) and the reaction mixture was stirred for 1 h at roomtemperature. The reaction mixture was then cooled to −78° C. andmethylmagnesium bromide (3.0 mol/L in diethyl ether) (0.14 mL, 0.41mmol) was added dropwise and the reaction mixture was stirred for 30mins at −78° C. An additional portion of methylmagnesium bromide (3.0mol/L in diethyl ether) (0.14 mL, 0.41 mmol) was added and the reactionmixture was stirred at −78° C. for an additional 15 min. An additionalportion of methylmagnesium bromide (3.0 mol/L in diethyl ether) (0.14mL, 0.41 mmol) was added an the reaction mixcture was stirred at −78° C.for an additional 10 min. The reaction mixture was warmed to roomtemperature, quenched by the addition of sat. aq. ammonium chloride andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was adsorbed onto silica and purified by flash columnchromatography with 0-10% MeOH in DCM to afford the desired compound asa beige foam (100 mg, 68%). MS-ESI: [M+H]⁺531.2

Step 4: (2S)-benzyl4-fluoro-4-methyl-2-(((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(INT-46-10)

To a solution of (2S)-benzyl4-hydroxy-4-methyl-2-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate(100 mg, 0.19 mmol) in dichloromethane (4 mL) cooled to −78° C. wasadded diethylaminosulfur trifluoride (0.050 mL, 0.38 mmol) and thereaction mixture was stirred at −78° C. for 2 h. The reaction mixturewas quenched by the careful addition of sat. aq. ammonium chloride andextracted with DCM (3×). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo. The residue wasadsorbed onto silica and purified by flash column chromatography with0-10% MeOH in DCM to afford the desired compound as a brown solid (72.5mg, 72%). MS-ESI: [M+H]⁺399.1

Step 5:(2S)-4-fluoro-4-methyl-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide(INT-46-11)

To a solution of (2S)-benzyl4-fluoro-4-methyl-2-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate(72.5 mg, 0.14 mmol) in ethanol (4 mL) was added palladium on carbon (10mass%) (14.5 mg, 0.014 mmol). Hydrogen was bubbled through the reactionmixture for 5 mins then the reaction was stirred at room temp under anatmosphere of hydrogen overnight. The reaction mixture was diluted withdichloromethane, filtered through celite, eluting with dichloromethaneand the filtrate was concentrated in vacuo. To the crude mixture wasadded palladium on carbon (10 mass%) (14.5 mg, 0.014 mmol) and ethanol(4 mL) and hydrogen was bubbled through the reaction mixture for 5 min.The mixture was then heated to 60° C. overnight under an atmosphere ofhydrogen. The reaction mixture was diluted with dichloromethane,filtered through celite, eluting with dichloromethane and the filtratewas concentrated in vacuo. The residue was adsorbed onto silica andpurified by flash column chromatography with 0-10% MeOH in DCM to affordthe desired compound as a yellow foam (37.6 mg, 69%). MS-ESI:[M+H]⁺533.2

Step 6:(2S,4R)-4-fluoro-1-((4-fluorophenyl)sulfonyl)-4-methyl-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

To(2S)-4-fluoro-4-methyl-N-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide(37.6 mg, 0.094 mmol) dissolved in dichloromethane (2 mL) was addedtriethylamine (0.026 mL, 0.19 mmol,) and 4-fluorobenzenesulfonylchloride (20.2 mg, 0.10 mmol) at room temperature for 4 h. The reactionmixture was diluted with DCM and water, the layers were separated andthe aqueous layer was extracted with DCM (2×). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo. The residue was adsorbed onto silica and purified by flash columnchromatography with 0-10% MeOH in DCM to afford the partially purifiedtitle compound. The residue was purified by RP-HPLC to yield the titlecompound (4.1 mg, 8%) as a white solid. MS-ESI: [M+H]⁺557.13

¹H NMR (400 MHz, DMSO) δ 9.20 (d, J=1.3 Hz, 1H), 9.07 (t, J=5.9 Hz, 1H),8.37-8.28 (m, 2H), 8.09 (d, J=1.4 Hz, 1H), 8.06-7.94 (m, 2H), 7.51-7.43(m, 4H), 4.57-4.41 (m, 2H), 4.32-4.23 (m, 1H), 3.74-3.48 (m, 2H),2.49-2.34 (m, 1H), 2.18-1.97 (m, 1H), 1.39 (d, J=20.8 Hz, 3H).

Example 47 Preparation of(2S,4R)-4-fluoro-N-(3-fluoro-5-(5-(trifluoromethyl)pyrazin-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide.

Step 1:(2S,4R)-4-fluoro-N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide(INT-47-6)

To a vial was added(2S,4R)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-4-methyl-pyrrolidine-2-carboxamide(INT-52-5) (340 mg, 0.69 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (58 mg, 0.069 mmol), bis(pinacolato)diboron (264mg, 1.04 mmol) and potassium acetate (204 mg, 2.08 mmol). 1,4-dioxane(10 mL) was added and nitrogen was bubbled through the solution for 3mins and the reaction mixture was heated to 85° C. for 16 h. Thereaction mixture was diluted with dichloromethane, filtered throughcelite, eluting with dichloromethane and the filtrate was concentratedin vacuo. The residue was adsorbed onto silica and purified by flashcolumn chromatography with 0-100% EtOAc in heptane to afford the desiredcompound as a brown oil (329 mg, 88%). MS-ESI: [M+H]⁺539.3

Step 2:(2S,4R)-4-fluoro-N-(3-fluoro-5-(5-(trifluoromethyl)pyrazin-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide

To a microwave vial was added(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-4-methyl-pyrrolidine-2-carboxamide(329 mg, 0.61 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (138 mg, 0.73mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(35 mg, 0.049 mmol), sodium carbonate (91 mg, 0.86 mmol) and potassiumacetate (85 mg, 0.86 mmol). Acetonitrile (8.0 mL) and water (1.6 mL)were added and nitrogen was bubbled through the reaction mixture for 4mins then heated to 140° C. in the microwave for 30 mins. The reactionmixture was diluted with dichloromethane, filtered through celite,eluting with dichloromethane and the filtrate was concentrated in vacuo.The residue was adsorbed onto silica and purified by flash columnchromatography with 0-100% EtOAc in heptane to afford the partiallypurified product. The residue was purified by RP-HPLC to yield the titlecompound (108 mg, 32%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 9.49 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H),8.92 (t, J=6.0 Hz, 1H), 8.05 (t, J=1.5 Hz, 1H), 8.00-7.92 (m, 3H),7.53-7.36 (m, 3H), 4.56-4.40 (m, 2H), 4.25-4.16 (m, 1H), 3.71-3.47 (m,2H), 2.44-2.34 (m, 1H), 2.14-1.93 (m, 1H), 1.38 (d, J=20.8 Hz, 3H).

Example 48: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

(2S,4R)-tert-butyl2-(((4-bromo-6-methylpyridin-2-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

To a solution of(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(100 mg, 0.43 mmol) and (4-bromo-6-methyl-2-pyridyl)methanaminehydrochloride (112.02 mg, 0.47 mmol) in N,N-dimethylformamide (1.7 mL)was added N,N-diisopropylethylamine (0.112 mL, 0.64 mmol) and HATU(199.62 mg, 0.51 mmol). The reaction mixture was stirred at RT 2 h.Thereaction was quenched with water and extracted with EtOAc. The organiclayers was dried with sodium sulfate, filtered, and concentrated viarotovap. The crude product was purified by flash chromatography(MeOH/DCM) to give 54 mg, 30.2% yield. LCMS (ESI) m/z:416.05 [M+H]+

(2S,4R)-tert-butyl4-fluoro-2-(((6-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

A solution of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (1.2 equiv.,0.3574 mmol), tert-butyl(2S,4R)-2-[(4-bromo-6-methyl-2-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(124 mg, 0.2979 mmol), cesium carbonate (194.1 mg, 0.04714 mL, 0.5957mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii)dichloromethane adduct (0.10 equiv., 0.02979 mmol) in acetonitrile (3.0mL) and water (1.5 mL) was degassed. The reaction mixture was heated at95° C. for 2 h. The reaction was filtered thru celite. The crude productwas purified by flash chromatography (MeOH/DCM) to give 70 mg, 48.6%yield. LCMS (ESI) m/z:484.15 [M+H]+

(2S,4R)-4-fluoro-N-((6-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-4-fluoro-2-[[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methylcarbamoyl]pyrrolidine-1-carboxylate(70 mg, 0.1448 mmol) in 1,4-dioxane (0.7239 mL) was added hydrochloricacid (4 mol/L) in 1,4-dioxane (0.3619 mL,). The reaction mixture wasstirred at RT 6 h. The reaction was concentrated and carried to nextstep. LCMS (ESI) m/z:384.1 [M+H]+

(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-fluoro-N-[[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide(55.5 mg, 0.1448 mmol) in dichloromethane (2.9 mL) was addedtriethylamine (0.404 mL, 2.896 mmol) then 4-fluorobenzenesulfonylchloride (42.26 mg, 0.2172 mmol). The reaction was stirred at RT 1 h.The reaction was concentrated and submitted for rHPLC to give 61.4 mg,78.32% yield.

1H NMR (400 MHz, DMSO) δ 9.51-9.41 (s, 2H), 9.06-8.95 (t, J=6.0 Hz, 1H),8.05-7.95 (m, 2H), 7.77-7.68 (dd, J=9.2, 1.5 Hz, 2H), 7.49-7.42 (m, 2H),5.31-5.09 (d, J=52.4 Hz, 1H), 4.56-4.40 (m, 2H), 4.30-4.20 (dd, J=9.9,7.1 Hz, 1H), 3.78-3.57 (m, 2H), 2.62-2.56 (s, 3H), 2.44-2.30 (m, 1H),2.24-2.00 (dddd, J=42.5, 14.0, 9.9, 3.4 Hz, 1H)., LCMS (ESI) m/z:542.13[M+H]+

Example 49 Preparation of(2S,4R)-4-fluoro-N-([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of (2,6-dichloropyridin-4-yl)boronic acid

n-BuLi (3 mL, 2.5 M in hexane, 1.50 equiv) was added dropwise into asolution of 2,6-dichloro-4-iodopyridine (1.40 g, 5.112 mmol, 1.00 equiv)in tetrahydrofuran (20 mL) at −78° C. under nitrogen. The resultingsolution was stirred for 30 min at −78° C. Trimethyl borate (580 mg,5.582 mmol, 1.10 equiv) was added at −78° C. and the reaction wasstirred for 1 h at −78° C. The resulting solution was stirred for anadditional 12 h at room temperature, quenched by 1.6 g of pinacol andthen AcOH (0.6 mL). The solids were filtered out and the liquid wasconcentrated under vacuum. This resulted in the title compound (1 g,crude) as a yellow solid.

Step 2: Preparation of2,6-dichloro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine

A mixture of 2-bromo-5-(trifluoromethyl)pyridine (800.00 mg, 3.54 mmol,1.00 equiv), (2,6-dichloropyridin-4-yl)boronic acid (1 g, 5.21 mmol,1.00 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (290 mg, 0.36 mmol, 0.10 equiv), andpotassium carbonate (1.96 g, 14.18 mmol, 4.00 equiv) in 1,4-dioxane (40mL) /water(2 mL) was stirred for 12 h at 120° C. under nitrogen. Theresulting solution was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1:100). This resulted in the titlecompound (680 mg, 66%) as a white solid.

Step 3: Preparation of2-chloro-6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine

A mixture of 2,6-dichloro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine(680.00 mg, 2.32 mmol, 1.00 equiv), and KF (134.80 mg, 2.32 mmol, 1.00equiv) in DMSO (5 mL) was stirred for 6 h at 140° C. The resultingsolution was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (1:100). This resulted in the title compound (600 mg, 93%) as awhite solid.

Step 4: Preparation of6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2-carbonitrile

A mixture of2-chloro-6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine (680.00mg, 2.46 mmol, 1.00 equiv), Zn(CN)₂ (288.71 mg, 2.46 mmol, 1.00 equiv),Pd₂(dba)₃.CHCl₃ (250 mg, 0.24 mmol, 0.10 equiv), dppf (410 mg, 0.74mmol, 0.30 equiv), and DMF (5 mL) was irradiated with microwave for 2 hat 100° C. under nitrogen. The resulting solution was diluted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1:100). This resulted in the title compound (610 mg, 93%) as a whitesolid.

Step 5: Preparation of[6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2-carbonitrile (300mg, 1.12 mmol, 1.00 equiv), and palladium on carbon (500 mg) in methanol(50 mL) was stirred for 30 min at room temperature under hydrogen. Thesolids were filtered out and the liquid was concentrated under vacuum toafford the title compound (300 mg, crude) as a yellow solid.

Step 6: tert-butyl(2S,4R)-4-fluoro-2-[([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(260.00 mg, 1.11 mmol, 1.00 equiv), DIEA (432.22 mg, 3.34 mmol, 3.00equiv), HATU (635.79 mg, 1.67 mmol, 1.50 equiv), and[6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methanamine(302.33 mg, 1.11 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) wasstirred for 2 h at room temperature. The resulting solution was dilutedwith ethyl acetate, washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (1:1). This resulted in the title compound (200 mg, 37%) as awhite solid.

Step 7:(2S,4R)-4-fluoro-N-([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-4-fluoro-2-[([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(200 mg, 0.41 mmol, 1.00 equiv) and saturated HCl in 1,4-dioxane (30 mL)was stirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound (150 mg, 94%) asa yellow solid.

Step 8:(2S,4R)-4-fluoro-N-([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-N-([6-fluoro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide(150.00 mg, 0.39 mmol, 1.00 equiv), triethylamine (117.87 mg, 1.16 mmol,3.00 equiv), and 4-fluorobenzene-1-sulfonyl chloride (151.13 mg, 0.78mmol, 2.00 equiv) in dichloromethane (20 mL) was stirred for 12 h atroom temperature. The reaction was diluted with water, extracted withdichloromethane, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). The crudeproduct (100 mg) was re-purified by Prep-HPLC to afford the titlecompound (54.1 mg, 26%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 9.05-9.02 (m, 1H), 8.42-8.34 (m,2H), 8.07 (s, 1H), 8.01-7.97 (m, 2H), 7.78 (s, 1H), 7.47-7.43 (m, 2H),5.21 (d, J=52.8 Hz, 2H), 4.46 (d, J=6 Hz, 2H), 4.26-4.22 (m, 1H),3.72-3.61 (m, 2H), 2.50-2.01 (m, 2H).

Example 50 Preparation of(2S,4R)-N-([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: ethyl 4-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate

A mixture of ethyl 4-methyl-1H-pyrazole-3-carboxylate (5 g, 32.43 mmol,1.0 equiv), 1-iodo-4-(trifluoromethyl)benzene (13.25 g, 48.71 mmol, 1.5equiv), CuI (600 mg, 3.15 mmol, 0.10 equiv), L-proline (750 mg, 6.51mmol, 0.20 equiv), and potassium carbonate (8.95 g, 64.76 mmol, 2.00equiv) in DMSO (150 mg) was stirred overnight at 100° C. under nitrogen.The reaction mixture was cooled, diluted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:5) to afford the title compound (5.3 g,55%) as a light yellow solid.

Step 2: ethyl 4-(bromomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate

A mixture of ethyl4-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate (5.78g, 19.38 mmol, 1.00 equiv), benzoyl benzenecarboperoxoate (469 mg, 1.94mmol, 0.10 equiv), and 1-bromopyrrolidine-2,5-dione (3.45 g, 19.38 mmol,1.00 equiv) in CCl₄(120 mL) was stirred overnight at 80° C. undernitrogen. The resulting solution was diluted with ethyl acetate, washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3) to afford thetitle compound (5 g, 68%) as a yellow solid.

Step 3: ethyl 4-(azidomethyl)-1-[4-(trifluoromethyl) phenyl]-pyrazole1H- -3-carboxylate

A mixture of ethyl 4-(bromomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate (5 g, 13.26 mmol, 1.00 equiv) andsodium azide (1 g, 15.38 mmol, 1.20 equiv) in N,N-dimethylformamide (80mL) was stirred for 2 days at room temperature. The reaction mixture wasthen quenched by water, extracted with ethyl acetate, washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:10). This resulted in the titlecompound (1.3 g, 29%) as light yellow oil.

Step 4: ethyl 4-(aminomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate hydrochloride

Into a 100-mL round-bottom flask purged and maintained with anatmosphere of H₂ was placed ethyl4-(azidomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate(1.15 g, 3.39 mmol, 1.00 equiv), ethanol (30 mL), palladium on carbon(500 mg), and hydrogen chloride (2 mL). The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out andthe liquid was concentrated under vacuum. This resulted in the titlecompound (1 g, 84%) as a light yellow solid.

Step 5: ethyl 4-([[(2S, 4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(824 mg, 3.53 mmol, 1.30 equiv), HATU (1.55 g, 4.08 mmol, 1.50 equiv),DIEA (1.05 g, 8.12 mmol, 3.00 equiv), and ethyl4-(aminomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylatehydrochloride (950 mg, 2.72 mmol, 1.00 equiv) in N, N-dimethylformamide(30 mL) was stirred for 1 h at room temperature. The reaction mixturewas diluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:3) to afford the title compound (1.35 g, 94%)as a light yellow solid.

Step 6: (2S,4R)-tert-butyl2-((3-carbamoyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate

A mixture of ethyl4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate(1.3 g, 2.46 mmol, 1.00 equiv) and NH₃/methanol (20 mL, 493.98 mmol,1.00 equiv) was stirred overnight at 70° C. The reaction mixture wasconcentrated under vacuum. This resulted in the title compound (1.1 g)as a light yellow solid which was used for the next step without anypurification.

Step 7: tert-butyl(2S,4R)-2-[([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylicacid (400 mg, 0.80 mmol, 1.00 equiv), TFAA (452 mg, 2.15 mmol, 2.00equiv), and TEA (320 mg, 3.16 mmol, 4.00 equiv) in dichloromethane (20mL) was stirred for 1 h at room temperature. The reaction mixture wasdiluted with water, extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:3)to afford the title compound (320 mg, 83%) as a light yellow solid.

Step 8:(2S,4R)-N-([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoropyrrolidine-2-carboxamide

A mixture of tert-butyl(2S,4R)-2-[([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(310 mg, 0.64 mmol, 1.00 equiv) and HCl/1,4-dioxane (20 mL) was stirredfor 5 h at room temperature. The solids were collected by filtration toafford the title compound (270 mg) as a white solid which was used forthe next step without any further purification.

Step 9:(2S,4R)-N-([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution(2S,4R)-N-([3-cyano-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (250 mg, 0.598 mmol, 1.00 equiv), TEA (267 mg, 2.639 mmol,4.00 equiv), 4-dimethylaminopyridine (8 mg, 0.065 mmol, 0.10 equiv), and4-fluorobenzene-1-sulfonyl chloride (152 mg, 0.781 mmol, 1.20 equiv) indichloromethane (10 mL) was stirred for 1 h at room temperature. Thereaction mixture was diluted with dichloromethane, washed with brine,dried over sodium sulfate, and concentrated under vacuum. The residuewas purified by Prep-HPLC to afford the title compound (124.8 mg, 39%)as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.88-8.85 (m, 1H), 8.76 (s, 1H), 8.09-8.06 (m,2H), 7.97-7.94 (m, 4H), 7.47-7.41 (m, 2H), 5.27-5.09 (d, J=52.5 Hz, 1H),4.38-4.34 (m, 2H), 4.16-4.10 (m, 1H), 3.71-3.57(m, 2H), 2.49-2.28(m,1H), 2.20-2.35(m, 1H).

Example 515-fluoro-2-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide.

Step 1: Preparation of ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

A mixture of cyclopenta-1,3-diene (16.5 g, 249.62 mmol, 1.00 equiv),ethyl 2-oxoacetate (75 mL, 756.70 mmol, 3.00 equiv), and NH₄Cl (200 g,3.74 mol, 15.00 equiv) in water (800 mL) was stirred for 16 h at roomtemperature. Sodium bicarbonate (5M) was employed to adjust the pH to 8.The resulting solution was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (58 g, crude) as brown oil.

Step 2: Preparation of 2-benzyl 3-ethyl2-azabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate

A mixture of ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (5 g,crude ,29.90 mmol, 1.00 equiv), Cbz-Cl (5 g, 29.31 mmol, 1.00 equiv),and TEA (6 g, 59.29 mmol, 2.00 equiv) in dichloromethane (30 mL) wasstirred for 16 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/5) to afford thetitle compound (1.8 g, 20%) as red oil.

Step 3: Preparation of 2-benzyl 3-ethyl5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylate

BH₃.THF (47.8 mL, 1M in THF, 1.1 equiv) was added dropwise into amixture of 2-benzyl 3-ethyl2-aza-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (12 g, 42.4 mmol, 1.00equiv) in tetrahydrofuran (150 mL) at −78° C. under nitrogen. After 1 hat room temperature sodium hydroxide (10%) (69.6 mL, 148 mmol, 3.50equiv) and H₂O₂ (30%) (22.6 mL, 212 mmol, 5.00 equiv) were added at 0°C. The resulting solution was stirred for 1 h at room temperature,quenched by water, and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/1). This resultedin the title compound (8.2 g, 62%) as yellow oil.

Step 4: Preparation of 2-benzyl 3-ethyl5-fluoro-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylate

DAST (4.99 g, 31 mmol, 2.2 equiv) was added dropwise into a mixture of2-benzyl 3-ethyl5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylateand 2-benzyl3-ethyl 6-hydroxy-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylate (4.5 g,14.1 mmol, 1.00 equiv) in DCM (100 mL) at −78° C. under nitrogen. Theresulting solution was stirred for 5 h at rt, quenched with water, andextracted with dichloromethane. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1/5). This resulted in the mixture of thetitle compounds and 2-benzyl 3-ethyl6-fluoro-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylate (1.2 g, 27%) asyellow oil.

Step 5: Preparation of ethyl5-fluoro-2-aza-bicyclo[2.2.1]heptane-3-carboxylate

A mixture of 2-benzyl 3-ethyl6-fluoro-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylat and 2-benzyl3-ethyl 5-fluoro-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylate(4.7 g,15.5 mmol, 1.00 equiv), and palladium on carbon (1.0 g) in methanol (50mL) was stirred for 16 h at room temperature under hydrogen. The solidswere filtered out and the liquid was concentrated under vacuum. Thisresulted in the title compound and its ethyl6-fluoro-2-aza-bicyclo[2.2.1]heptane-3-carboxylate(2.5 g, 86%) as yellowoil.

Step 6: Preparation of ethyl5-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylate

A mixture of two position isomers (2.5 g, 13.3 mmol, 1.00 equiv), TEA(2.7 g, 26.68 mmol, 2.00 equiv), and 4-fluorobenzene-1-sulfonyl chloride(3.1 g, 15.93 mmol, 1.20 equiv) in dichloromethane (50 mL) was stirredfor 2 h at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1/5) to afford the mixture of thetitle compound and ethyl6-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylate(2.5g, 54%) as a yellow solid.

Step 7: Preparation of 5-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid

A mixture of ethyl5-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylateand ethyl6-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylate(2.5g, 7.24 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) and LiOH (522 mg,21.80 mmol, 3.00 equiv) in water (50 mL) was stirred for 16 h at roomtemperature. The pH value of the solution was adjusted to 5 with citricacid. The resulting solution was extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in a mixture of the title compound and6-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylicacid (2.0 g, 87%) as a yellow solid.

Step 8: Preparation of5-fluoro-2-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide

A mixture of5-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylicacid and6-fluoro-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxylicacid (2.0 g, 6.3 mmol, 1.00 equiv),(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanaminel (1.6 g,6.3 mmol, 1.0 equiv), HATU (3.6 g, 9.5 mmol, 1.50 equiv), and DIPEA (1.6g, 12.6 mmol, 2.0 equiv) in DMF (50 mL) was stirred for 16 h at roomtemperature. The reaction mixture was diluted with water and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. The cruderesidue was purified by Prep_SFC to afford the title compound (137.3 mg,3.9%). t_(R)=0.90 min (Lux 3 μm Cellulose-4, 4.6×100 mm, 3 μm, MeOH(0.1% DEA)=30%, 4 ml/min).

¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H), 9.29 (d, J=0.9 Hz, 1H), 8.91(t, J=6.3 Hz, 1H),8.73-8.70 (m, 1H), 8.09-7.99 (m, 4H),7.38 (t, J=9.0Hz,2H), 4.85-4.95 (d, J=59.7 Hz, 1H),4.47 (t, J=5.1Hz, 2H), 4.08 (s, 1H),3.93 (s, 1H), 2.98 (d, J=3.9Hz, 1H), 2.15 (s, J=9.6Hz, 1H), 1.79-1.56(m, 3H).

6-fluoro-2-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[2.2.1]heptane-3-carboxamidewas also isolated (732.9 mg, 20.9%) as a white solid. t_(R)=1.07 min(Lux 3μm Cellulose-4, 4.6×100 mm, 3 μm, MeOH (0.1% DEA)=30%, 4 ml/min).

¹H NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 1H), 9.29 (s, 1H), 8.91 (t, J=5.7Hz, 1H),8.73 (d, J=8.1Hz, 1H), 8.13-7.99 (m, 4H), 7.38 (t, J=9.0Hz,2H),4.85-4.65 (d, J=59.7 Hz, 1H), 4.54-4.39 (m, 2H), 4.08 (s, 1H), 3.93(s, 1H), 2.79 (d, J=3.6Hz, 1H), 2.15 (s, J=9.9 Hz, 1H), 1.91-1.39 (m,3H).

The F position (5-F or 6-F) for the above two position isomers wasarbitrary assigned. The 2-proline stereochemistry is as shown.

Example 52 Preparation of(2S,4R)-4-fluoro-N-(3-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide.

Step 1: (S)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-oxopyrrolidine-1-carboxylate(INT-52-2)

To a round bottomed flask was added(2S)-1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2.35 g,10.2 mmol), (3-bromo-5-fluorophenyl)methanamine (2.00 g, 9.31 mmol) andHATU (3.97 g, 10.2 mmol). Dichloromethane (47 mL) was added followed byN,N-diisopropylethylamine (3.25 mL, 18.6 mmol) and the reaction mixturewas stirred overnight at room temperature. The reaction was quenchedwith sat. aq. sodium bicarbonate and extracted with DCM (3×). Thecombined organic extracts were washed with water (1×), brine (1×) thendried over sodium sulfated, filtered and concentrated in vacuo. Theresidue was adsorbed onto silica and purified by flash columnchromatography with 0-100% EtOAc in Heptane to afford the desiredcompound as a beige solid (3.47 g, 90%). MS-ESI: [M+H]⁺414.9

Step 2: (2S,4R)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate(INT-52-3)

To a solution of (S)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-oxopyrrolidine-1-carboxylate(1.94 g, 4.67 mmol) in tetrahydrofuran (40 mL) was added Lanthanum(III)chloride bis(lithium chloride) complex solution 0.6 M in THF (8.6 mL,5.14 mmol) and the reaction mixture was stirred for 1 h at roomtemperature. The reaction mixture was then cooled to −78° C. andmethylmagnesium bromide (3.0 mol/L) in diethyl ether (7.0 mL, 21.0 mmol)was added dropwise and the reaction mixture was stirred for 30 mins at−78° C. An additional portion of methylmagnesium bromide (3.0 mol/L) indiethyl ether (7.0 mL, 21.0 mmol) was added and the mixture was stirredat −78° C. for an additional 30 min. An additional portion ofmethylmagnesium bromide (3.0 mol/L) in diethyl ether (7.0 mL, 21.0 mmol)was added and the mixture was stirred at −78° C. for an additional 15min. The reaction mixture was warmed to room temperature, quenched bythe addition of sat. aq. ammonium chloride and extracted with EtOAc(3×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue wasadsorbed onto silica and purified by flash column chromatography with0-100% EtOAc in heptane to afford the desired compound as a beige foam(1.29 g, 64%). MS-ESI: [M−100]⁺331.0

Step 3: (2S,4R)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-fluoro-4-methylpyrrolidine-1-carboxylate(INT-52-3)

To a solution of (2S,4R)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate(337 mg, 0.781 mmol) in dichloromethane (10 mL) cooled to −78° C. wasadded diethylaminosulfur trifluoride (0.21 mL, 1.56 mmol) and thereaction mixture was stirred at −78° C. for 30 min. The reaction mixturewas quenched by the careful addition of sat. aq. ammonium chloride andextracted with DCM (3×). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo. The residue wasadsorbed onto silica and purified by flash column chromatography with0-10% MeOH in DCM to afford the desired compound as a brown solid (314.7mg, 93%). MS-ESI: [M−H]⁺433.1

Step 4:(2S,4R)-N-(3-bromo-5-fluorobenzyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide(INT-52-5)

To a solution of (2S,4R)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-fluoro-4-methylpyrrolidine-1-carboxylate(315 mg, 0.7270 mmol) in dichloromethane (4 mL) was added hydrochloricacid (4 mol/L) in 1,4-dioxane (1.5 mL, 6.0 mmol). The reaction mixturewas stirred at room temp for 2 h then concentrated in vacuo. The cruderesidue was dissolved in dichloromethane (6 mL) and triethylamine (0.30mL, 2.2 mmol) and 4-fluorobenzenesulfonyl chloride (156 mg, 0.8005mmol,) were added and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with DCM andwater, the layers were separated and the aqueous layer was extractedwith DCM (2×). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was adsorbedonto silica and purified by flash column chromatography with 0-10% MeOHin DCM to afford the title compound as a pale yellow foam (172.4 mg,48%). MS-ESI: [M−H]⁻493.1

Step 5:(2S,4R)-4-fluoro-N-(3-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide

To a microwave vial was added(2S)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-4-methyl-pyrrolidine-2-carboxamide(60 mg, 0.12 mmol), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (33mg, 0.17 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(6.9 mg, 0.0098 mmol), sodium carbonate (18 mg, 0.17 mmol) and potassiumacetate (17 mg, 0.17 mmol). Acetonitrile (0.8 mL) and water (0.16 mL)were added and nitrogen was bubbled through the reaction mixture for 3mins then heated to 140° C. in the microwave for 30 mins. The reactionmixture was diluted with dichloromethane, filtered through celite,eluting with dichloromethane and the filtrate was concentrated in vacuo.The residue was adsorbed onto silica and purified by flash columnchromatography with 0-100% EtOAc in heptane to afford the partiallypurified product. The residue was further purified by RP-HPLC to yieldthe title compound as a white solid (43.3 mg, 68%). MS-ESI: [M+H]⁺559.12

¹H NMR (400 MHz, DMSO) δ 9.42 (s, 2H), 8.92 (t, J=6.0 Hz, 1H), 8.02-7.92(m, 2H), 7.78-7.69 (m, 2H), 7.51-7.40 (m, 2H), 7.40-7.32 (m, 1H),4.56-4.38 (m, 2H), 4.25-4.16 (m, 1H), 3.71-3.46 (m, 2H), 2.48-2.31 (m,1H), 2.15-1.94 (m, 1H), 1.38 (d, J=20.7 Hz, 3H).

Example 53 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.51-9.44 (s, 2H), 9.08-8.98 (t, J=6.0 Hz, 1H),8.78-8.69 (dd, J=5.2, 0.8 Hz, 1H), 8.04-7.96 (m, 2H), 7.94-7.89 (dd,J=1.7, 0.9 Hz, 1H), 7.89-7.83 (dd, J=5.2, 1.8 Hz, 1H), 7.51-7.40 (m,2H), 5.30-5.09 (d, J=52.5 Hz, 1H), 4.62-4.46 (m, 2H), 4.29-4.18 (dd,J=9.9, 7.1 Hz, 1H), 3.78-3.57 (m, 2H), 2.43-2.35 (m, 1H), 2.23-2.02 (m,1H)., LCMS (ESI) m/z:528.11 [M+H]+

Example 54: Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(5-(trifluoromethyl)pyrazin-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

To a microwave vial was added(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide1 (216 mg, 0.41 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (105 mg,0.58 mmol), Pd (amphos)Cl₂ (23 mg, 0.03 mmol), sodium carbonate (61 mg,0.58 mmol) and potassium acetate (57 mg, 0.58 mmol), acetonitrile (0.8mL) and water (0.16 mL). The reaction mixture was purged with nitrogengas for 3 minutes and then heated to 140° C. in the microwave for 30minutes. Upon cooling to room temperature, the resulting mixture wasfiltered through a thin layer of celite, washed with water and extractedwith ethyl acetate. The combined organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to afford the title compound (99 mg, 44%)as a white solid. LC/MS (ESI+): m/z 545.5 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J=1.5 Hz, 1H), 9.21 (d, J=1.4 Hz,1H), 8.92 (t, J=5.9 Hz, 1H), 8.36-8.13 (m, 2H), 8.08-7.88 (m, 2H), 7.44(td, J=8.6, 1.3 Hz, 3H), 4.54-4.35 (m, 2H), 4.22 (dd, J=9.8, 7.2 Hz,1H), 3.78-3.49 (m, 2H), 2.50-2.27 (m, 2H), 2.09 (dddd, J=42.1, 13.8,9.8, 3.5 Hz, 1H).

Example 55 Preparation of(2R,3S)-N-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-3-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

(2R,3S)-tert-butyl2-(((6-(4-(difluoromethyl)phenyl)pyrimidin-4-yl)methyl)carbamoyl)-3-fluoropyrrolidine-1-carboxylate

To a solution of tert-butyl(2S,3R)-2-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methylcarbamoyl]-3-hydroxy-pyrrolidine-1-carboxylate(360 mg, 0.8027 mmol) in dichloromethane (16.0 mL) at 0° C. was addeddropwise diethylaminosulfur trifluoride (388.1 mg, 0.3187 mL, 2.408mmol). The reaction was warmed to RT 1 h. The reaction was quenched withwater and extracted with EtOAc. The organic layers was dried with sodiumsulfate, filtered, and concentrated via rotovap. The crude product wascarried to next step. LCMS (ESI) m/z:451.20 [M+H]+

(2R,3S)-N-((6-(4-(difluoromethyl)phenyl)pyrimidin-4-yl)methyl)-3-fluoropyrrolidine-2-carboxamide

A solution of tert-butyl(2R,3S)-2-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methylcarbamoyl]-3-fluoro-pyrrolidine-1-carboxylate(361 mg, 0.8015 mmol) in hydrochloric acid (4 mol/L) in 1,4-dioxane(2.00 mL) and 1,4-dioxane (3.00 mL) was stirred at RT 18 h. The reactionwas concentrated and carried to next step. LCMS (ESI) m/z:351.05 [M+H]+

(2R,3S)-N-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-3-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

To a solution of(2R,3S)-N-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-3-fluoro-pyrrolidine-2-carboxamide(281 mg, 0.8022 mmol) in dichloromethane (8.027 mL) was addedtriethylamine (2.24 mL, 16.05 mmol) and 4-fluorobenzenesulfonyl chloride(187.5 mg, 0.9632 mmol). The reaction mixture was stirred at RT 1 h. Thecrude product was concentrated and purified by flash chromatography(MeOH/DCM) then submitted for rHPLC to give 113 mg, 27.69% .

1H NMR (400 MHz, DMSO) δ 9.25-9.21 (d, J=1.3 Hz, 1H), 9.21-9.14 (t,J=6.0 Hz, 1H), 8.40-8.31 (m, 2H), 8.09-8.00 (m, 3H), 7.77-7.70 (dt,J=8.5, 1.1 Hz, 2H), 7.56-7.47 (m, 2H), 7.28-6.96 (m, 1H), 5.32-5.12 (m,1H), 4.61-4.38 (m, 3H), 3.74-3.63 (ddd, J=9.7, 6.7, 1.9 Hz, 1H),3.23-3.12 (m, 1H), 2.29-2.08 (m, 2H)., LCMS (ESI) m/z:509.13 [M+H]+

Example 56 Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Following the same procedure of Example 183, step 4: The title compound(2S,4R)-4-fluoro-N-(2-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide(849 mg, 68%) was prepared from(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide1 (1.1 g, 2.3 mmol), [5-(trifluoromethyl)pyrimidin-2-yl]boronic acid(487 mg, 2.5 mmol), cesium carbonate 1 M in water (3.2 mL, 3.2 mmol),Pd(dppf)Cl₂ (192 mg, 0.23 mmol) in acetonitrile (4 mL). LC/MS (ESI+):m/z 545.5 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.90 (t, J=5.9 Hz, 1H),8.06-7.79 (m, 3H), 7.45 (td, J=8.8, 1.4 Hz, 2H), 5.19 (d, J=52.6 Hz,1H), 4.47 (d, J=5.9 Hz, 2H), 4.29-4.10 (m, 1H), 3.75-3.67 (m, 1H),3.67-3.51 (m, 1H), 2.47-2.29 (m, 1H), 2.09 (dddd, J=42.5, 13.8, 10.0,3.4 Hz, 1H).

Example 57 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.Step 1:(2S,4R)-N-((2-(2-(benzyloxy)-4-(trifluoromethyl)phenyl)pyridin-4-yl)methyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide

The title compound (72 mg, 64%) was prepared following the Suzukicoupling procedure of Example 8, Step 1 from(2S,4R)-N-[(2-bromo-4-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(82 mg, 0.18 mmol), 2-benzyloxy-4-(trifluoromethyl)phenylboronic acid(69 mg, 0.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.02mmol) and aqueous Cs2CO3 (0.22 mL, 0.22 mmol, 1.0 mol/L) in acetonotrile(4 mL). LCMS (ESI_Formic_MeCN): [MH⁺]=632.

Step 2: (2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide

(2S,4R)-N-[[2-[2-benzyloxy-4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(36 mg, 0.06 mmol) in methanol (4 ml) was hydrogenated at 1 atm overpalladium on carbon (10%) (22 mg) for 2 hours. The mixture was filteredthrough Celite and the filtrate concentrated in vacuum. The residue wassubjected to RP HPLC purification to afford 22 mg (71%) of the titlecompound.

1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.02 (t, J=6.0 Hz, 1H), 8.64(dd, J=5.3, 0.7 Hz, 1H), 8.32-8.22 (m, 2H), 8.06-7.97 (m, 2H), 7.53-7.43(m, 3H), 7.27-7.21 (m, 1H), 7.20-7.14 (m, 1H), 5.21 (d, J=52.2 Hz, 1H),4.61-4.44 (m, 2H), 4.21 (dd, J=9.9, 7.1 Hz, 1H), 3.81-3.57 (m, 2H),2.49-2.36 (m, 1H), 2.11 (dddd, J=42.5, 13.8, 10.0, 3.4 Hz, 1H).

Example 58 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]pyrazol-4-yl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of ethyl3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazole-4-carboxylate

A mixture of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (1.116 g, 6.56mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL), L-Proline (151 mg,1.31 mmol, 0.20 equiv), CuI (128 mg, 0.67 mmol, 0.10 equiv),2-chloro-5-(trifluoromethyl)pyrazine (1.19 g, 6.52 mmol, 1.00 equiv),and potassium carbonate (2.72 g, 19.68 mmol, 3.00 equiv) was stirredovernight at 100° C. under nitrogen. The solids were filtered out. Thefiltrate was diluted with 500 mL of ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with ethylacetate/petroleum ether (5:100) to afford the title compound (1 g, 48%)as an off-white solid.

Step 2: Preparation of[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methanol

DIBAL-H (6 mL, 6.33 mmol, 2.10 equiv) was added dropwise into a solutionof ethyl3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazole-4-carboxylate(950 mg, 3.00 mmol, 1.00 equiv) in dichloromethane (50 mL) at −78° C.under nitrogen. After 3 h at −78° C. the reaction was quenched bymethanol, diluted with brine, extracted with dichloromethane, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (10:100) to afford the title compound (600 mg, 73%) as a whitesolid.

Step 3: Preparation of2-([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)-2,3-dihydro-1H-isoindole -1,3-dione

DIAD (267 mg, 1.32 mmol, 1.20 equiv) was added dropwise into a solutionof[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methanol(300 mg, 1.09 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindole-1,3-dione (242mg, 1.64 mmol, 1.50 equiv), and PPh₃ (577 mg, 2.20 mmol, 2.00 equiv) intetrahydrofuran (30 mL) at 0° C. under nitrogen. After 5 h at roomtemperature the resulting mixture was concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (5:100) to afford the title compound (500 mg) asa white solid.

Step 4: Preparation of[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methanamine

A solution of2-([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(400 mg, 0.99 mmol, 1.00 equiv) and NH₂NH₂.H₂O (1 mL, 20.58 mmol, 41.50equiv) in methanol (5 mL) was stirred overnight at room temperature. Thereaction mixture was concentrated under vacuum and the residue wasdissolved in ethyl acetate. The solids were filtered out. The filtratewas concentrated under vacuum to afford the title compound (210 mg, 77%)as light yellow oil.

Step 5: Preparation of tert-butyl(2S,4R)-4-fluoro-2-[([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methanamine(210 mg, 0.77 mmol, 1.00 equiv),(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(197 mg, 0.84 mmol, 1.10 equiv), HATU (437 mg, 1.15 mmol, 1.50 equiv),and DIEA (248 mg, 1.92 mmol, 2.50 equiv) in N,N-dimethylformamide (5 mL)was stirred overnight at room temperature. The mixture was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:10) to afford the title compound(190 mg, 51%) as light yellow oil.

Step 6: Preparation of(2S,4R)-4-fluoro-N-([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-4-fluoro-2-[([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(100 mg, 0.205 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (5 mL) was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum to afford the titlecompound (79 mg, 91%) as light yellow oil.

Step 7: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]pyrazol-4-yl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-N-([3-methoxy-1-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (60 mg, 0.141 mmol, 1.00 equiv),4-fluorobenzene-1-sulfonyl chloride (36 mg, 0.185 mmol, 1.20 equiv),4-dimethylaminopyridine (2 mg, 0.016 mmol, 0.20 equiv), and TEA (60 mg,0.593 mmol, 3.80 equiv) in dichloromethane (5 mL) was stirred overnightat room temperature. The mixture was diluted with water and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/5) to afford the title compound (30.6 mg,38%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H),7.88-7.33 (m, 2H), 7.36-7.18 (m, 2H), 5.11-4.94 (d, J=26.1 Hz, 1H),4.44-4.22 (m, 3H), 4.19 (s, 3H), 3.95-3.38 (m, 1H), 3.69-3.50 (m, 1H),2.50-2.19 (m, 2H).

Example 59 Preparation of(2S,4R)-N-[[6-[4-(difluoromethyl)-3-fluoro-phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 42.

1H NMR (400 MHz, DMSO) δ 9.26-9.22 (d, J=1.3 Hz, 1H), 9.15-9.07 (t,J=6.0 Hz, 1H), 8.21-8.09 (m, 3H), 8.07-8.00 (m, 2H), 7.82-7.74 (t, J=7.7Hz, 1H), 7.52-7.44 (m, 2H), 7.40-7.11 (m, 1H), 5.31-5.12 (m, 1H),4.59-4.42 (m, 2H), 4.29-4.22 (dd, J=10.0, 7.1 Hz, 1H), 3.76-3.58 (m,2H), 2.46-2.36 (m, 1H), 2.24-2.02 (dddd, J=42.6, 13.6, 10.0, 3.3 Hz,1H)., LCMS (ESI) mh:527.12 [M+H]+

Example 60 Preparation of(2S,4R)-N-[[2-chloro-6-[6-(difluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure ofExample 62.

¹H NMR (400 MHz, DMSO) δ 9.36-9.28 (dd, J=2.3, 0.8 Hz, 1H), 9.07-8.97(t, J=6.0 Hz, 1H), 8.65-8.57 (dd, J=8.2, 2.2 Hz, 1H), 8.14-8.09 (d,J=1.2 Hz, 1H), 8.04-7.96 (m, 2H), 7.86-7.80 (m, 1H), 7.61-7.55 (d, J=1.0Hz, 1H), 7.52-7.43 (m, 2H), 7.20-6.87 (m, 1H), 5.31-5.10 (d, J=52.4 Hz,1H), 4.58-4.40 (m, 2H), 4.24-4.13 (dd, J=10.0, 7.1 Hz, 1H), 3.79-3.59(m, 2H), 2.46-2.36 (m, 1H), 2.22-1.99 (m, 1H)., LCMS (ESI) m/z:543.09[M+H]+

Example 61 Preparation of(2S,4R)-N-[[2,6-bis[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure ofExample 62.

1H NMR (400 MHz, DMSO) δ 9.96-9.82 (s, 4H), 9.21-9.09 (t, J=6.0 Hz, 1H),8.42-8.29 (s, 2H), 8.10-7.98 (m, 2H), 7.55-7.41 (m, 2H), 5.31-5.12 (d,J=52.2 Hz, 1H), 4.72-4.53 (m, 2H), 4.29-4.18 (dd, J=10.1, 7.0 Hz, 1H),3.80-3.60 (m, 2H), 2.47-2.37 (m, 1H), 2.26-2.03 (m, 1H)., LCMS (ESI)m/z:674.2 [M+H]+

Example 62 Preparation of(2S,4R)-N-[[2-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

(2S,4R)-tert-butyl2-(((2,6-dichloropyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

To a solution of(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(500 mg, 2.1437 mmol) and 2,6-dichloropyridine-4-methylamine (426 mg,2.36 mmol) in N,N-dimethylformamide (8.6 mL) was addedN,N-diisopropylethylamine (0.561 mL, 3.2156 mmol) and HATU (998.09 mg,2.5725 mmol). The reaction mixture was stirred at RT 2 h.The reactionwas quenched with water and extracted with EtOAc. The organic layers wasdried with sodium sulfate, filtered, and concentrated via rotovap. Thecrude product was carried to next step. LCMS (ESI) m/z:392.10 [M+H]+

(2S,4R)-tert-butyl2-(((2-chloro-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

A solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(0.5 equiv., 0.2295 mmol), tert-butyl(2S,4R)-2-[(2,6-dichloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(180 mg, 0.4589 mmol), cesium carbonate (299.1 mg, 0.07263 mL, 0.9179mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii)dichloromethane adduct (0.10 equiv., 0.04589 mmol) in acetonitrile (3.0mL) and water (1.5 mL) was degassed. The reaction mixture was heated at95° C. for 2 h. The reaction was filtered thru celite. The crude productwas purified by flash chromatography (MeOH/DCM) to give 84 mg, 36.3%yield. LCMS (ESI) m/z:504.20 [M+H]+

(2S,4R)-N-((2-chloro-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-2-[[2-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(84 mg, 0.1667 mmol) in 1,4-dioxane (860.2 mg, 0.8335 mL, 9.763 mmol)was added hydrochloric acid (4 mol/L) in 1,4-dioxane (438 mg, 0.4167 mL,1.667 mmol). The reaction mixture was stirred at RT 6 h. The reactionwas concentrated and carried to next step. LCMS (ESI) m/z:404.0 [M+H]+

(2S,4R)-N-[[2-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

To a solution of(2S,4R)-N-[[2-chloro-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-4-fluoro-pyrrolidine-2-carboxamide(B) in dichloromethane (3.3 mL) was added triethylamine (337.4 mg, 0.465mL, 3.334 mmol) then 4-fluorobenzenesulfonyl chloride (C, 48.66 mg,0.2500 mmol). The reaction was stirred at RT 1 h. The reaction wasconcentrated and submitted for rHPLC 32.1 mg, 34.3% yield.

1H NMR (400 MHz, DMSO) δ 9.64-9.57 (s, 2H), 9.11-9.01 (t, J=6.0 Hz, 1H),8.23-8.16 (d, J=1.1 Hz, 1H), 8.05-7.97 (m, 2H), 7.70-7.63 (q, J=0.9 Hz,1H), 7.53-7.43 (m, 2H), 5.30-5.10 (d, J=52.6 Hz, 1H), 4.59-4.41 (m, 2H),4.23-4.13 (dd, J=10.1, 7.1 Hz, 1H), 3.79-3.58 (m, 2H), 2.47-2.36 (m,1H), 2.21-1.98 (m, 1H)., LCMS (ESI) m/z:562.2 [M+H]+

Example 63(2S,4R)-N-[[6-[4-(difluoromethyl)phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 42.

1H NMR (400 MHz, DMSO) δ 9.26-9.20 (d, J=1.2 Hz, 1H), 9.12-9.04 (m, 1H),8.37-8.32 (dd, J=7.7, 1.2 Hz, 1H), 8.17-8.10 (m, 1H), 8.07-8.00 (m, 2H),7.73-7.67 (d, J=8.2 Hz, 1H), 7.54-7.45 (m, 2H), 7.35-7.28 (m, 1H),7.26-6.94 (m, 2H), 5.31-5.12 (d, J=52.3 Hz, 1H), 4.60-4.42 (m, 2H),4.31-4.21 (m, 1H), 3.79-3.59 (m, 2H), 2.46-2.31 (m, 1H), 2.23-2.01 (m,1H)., LCMS (ESI) m/z:509.2 [M+H]+

Example 64(2S,4R)-N-[[6-[4-(difluoromethoxy)phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 42.

1H NMR (400 MHz, DMSO) δ 9.20-9.14 (d, J=1.2 Hz, 1H), 9.11-9.04 (t,J=6.0 Hz, 1H), 8.33-8.25 (m, 2H), 8.08-8.01 (m, 3H), 7.51-7.44 (m, 2H),7.32-7.26 (m, 2H), 5.32-5.11 (d, J=52.3 Hz, 1H), 4.50-4.45 (dd, J=5.8,3.7 Hz, 2H), 4.29-4.21 (m, 1H), 3.76-3.62 (m, 2H), 2.46-2.36 (m, 1H),2.25-2.01 (m, 1H)., LCMS (ESI) m/z:525.2 [M+H]+

Example 65:(2S,4R)-4-fluoro-N-[[5-fluoro-4-[5-fluoro-6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of 5-bromo-3-fluoro-2-iodopyridine

A mixture of 5-bromo-2-chloro-3-fluoropyridine (5.00 g, 23.76 mmol,1.000 equiv), NaI (10.68 g, 71.25 mmol, 3.0 equiv), andchlorotrimethylsilane (2.58 g, 23.748 mmol, 1.000 equiv) in CH₃CN (20mL) was stirred for 2 h at 80° C. The reaction was then quenched bywater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:100) to afford the title compound (1.5 g, 21%) as a yellowsolid.

Step 2: Preparation of 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine

A mixture of 5-bromo-3-fluoro-2-iodopyridine (1.20 g, 3.98 mmol, 1.00equiv), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (5.35 g, 27.85mmol, 7.00 equiv), CuI (5.30 g, 27.83 mmol, 7.00 equiv), and DMF (20 mL)was stirred for 12 h at 70° C. under nitrogen. The reaction was thenquenched by water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:200) to afford the title compound (200 mg,21%) as yellow oil.

Step 3: Preparation of [5-fluoro-6-(trifluoromethyl)pyridin-3-yl]boronicacid

A mixture of 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (200.00 mg,0.82 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(312.24 mg, 1.23 mmol, 1.50 equiv), Pd(dppf)Cl₂ (29.99 mg, 0.04 mmol),and KOAc (241.35 mg, 2.46 mmol, 3.00 equiv) in 1,4-dioxane (5 mL) wasstirred for 3 h at 100° C. under nitrogen. The reaction was thenquenched by water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (400 mg, crude) as a black solid.

Step 4:(2S,4R)-4-fluoro-N-[[5-fluoro-4-[5-fluoro-6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-[(4-bromo-5-fluoropyridin-2-yl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrroli-dine-2-carboxamide(150.00 mg, 0.314 mmol, 1.000 equiv),[5-fluoro-6-(trifluoromethyl)pyridin-3-yl]boronic acid (400 mg, 1.915mmol, 3.000 equiv), Pd(dppf)Cl₂ (22.95 mg, 0.031 mmol, 0.100 equiv),potassium carbonate (130.03 mg, 0.941 mmol, 3.000 equiv), and1,4-dioxane (20 mL)/water (2 mL) was stirred for 3 h at 100° C. undernitrogen. The resulting solution was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:1) to afford the title compound (57.3mg, 32%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.07-9.03 (m, 1H), 8.89 (s, 1H), 8.74 (s,1H), 8.40 (d, J=11.4 Hz, 1H), 8.00-7.95 (m, 2H), 7.77 (d, J=6.3 Hz, 1H),7.48-7.42 (m, 2H), 5.19 (d, J=52 Hz, 1H),4.57-4.42 (m, 2H), 4.23-4.18(m, 1H), 3.71-3.54 (m, 2H), 2.49-1.99 (m, 2H).

Example 66(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-4-[4-(trifluoromethoxy)-1-piperidyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of piperidin-4-ol hydrochloride

A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5 g, 24.84mmol, 1.00 equiv) and HCl (saturated solution in 30 mL of 1,4-dioxane)was stirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound (3.4 g, 99%) asan off-white solid.

Step 2: Preparation of benzyl 4-hydroxypiperidine-1-carboxylate

Benzyl chloroformate (4.64 g, 27.199 mmol, 1.101 equiv) was addeddropwise into a mixture of piperidin-4-ol hydrochloride (3.4 g, 24.71mmol, 1.0 equiv), sodium hydroxide (2.17 g, 54.25 mmol, 2.2 equiv), andwater (55 mL)/1,4-dioxane (55 mL). The resulting solution was stirredfor 30 min at room temperature. The mixture was diluted with water. ThepH value of the mixture was adjusted to 2 with 1N HCl. The resultingsolution was extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:2). This resulted in the title compound (4.4 g, 76%) ascolorless oil.

Step 3: Preparation of benzyl4-[[(methylsulfanyl)methanethioyl]oxy]piperidine-1-carboxylate

Sodium hydride (960 mg, 60% in mineral oil, 2.139 equiv) was added inseveral batches into a solution of benzyl4-hydroxypiperidine-1-carboxylate (4.4 g, 18.70 mmol, 1.0 equiv) inN,N-dimethylformamide (50 mL) at 0° C. under nitrogen. After 0.5 h at 0°C. carbon disulfide (5.8 g, 76.174 mmol, 4.07 equiv) was added dropwise.The resulting mixture was stirred for 0.5 h at 0° C. and CH₃I (4.0 g,28.181 mmol, 1.51 equiv) was then added dropwise. After 1 h at 0° C. thereaction was then quenched by water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by silica gel column eluting withethyl acetate/petroleum ether (1/10). This resulted in the titlecompound (3 g, 49%) as colorless oil.

Step 4: Preparation of benzyl4-(trifluoromethoxy)piperidine-1-carboxylate

HF pyridine (20 g, 201.80 mmol, 21.89 equiv) and benzyl4-[[(methylsulfanyl)methanethioyl]oxy]piperidine-1-carboxylate (3 g,9.22 mmol, 1.0 equiv) in 10 mL of dichloromethane were added insequentially into a mixture of1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (7.9 g, 27.630 mmol,2.997 equiv) in dichloromethane (100 mL) at −78° C. under nitrogen. Theresulting solution was stirred for 12 h at room temperature. Thereaction was then quenched by saturated sodium bicarbonate, extractedwith dichloromethane, washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1/10) toafford the title compound (1.5 g, 54%) as light yellow oil.

Step 5: Preparation of 4-(trifluoromethoxy)piperidine

A mixture of benzyl 4-(trifluoromethoxy)piperidine-1-carboxylate (1.1 g,3.63 mmol, 1.0 equiv) and palladium on carbon (1 g, 9.397 mmol, 2.591equiv) in methanol (50 mL) was stirred for 12 h at room temperature. Thesolids were filtered out and the liquid was concentrated under vacuum.The residue was dissolved with saturated solution of HCl in 1,4-dioxaneand concentrated under vacuum. This resulted in the title compound (0.7g, crude) as a light yellow solid.

Step 6: Preparation of(2S,4R)-4-fluoro-N-([5-fluoro-4-[4-(trifluoromethoxy)piperidin-1-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of 4-(trifluoromethoxy)piperidine hydrochloride (200 mg, 0.973mmol, 1.0 equiv), potassium carbonate (410 mg, 2.967 mmol, 3.05 equiv),(2S,4R)-N-[(4-bromo-5-fluoropyridin-2-yl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(231 mg, 0.483 mmol, 0.5 equiv), Pd₂(dba)₃.CHCl₃ (100 mg, 0.097 mmol,0.099 equiv), and XantPhos (112 mg, 0.194 mmol, 0.2 equiv) in toluene(10 mL) was stirred for 12 h at 100° C. under nitrogen. The reactionmixture was concentrated under vacuum. The residue was dissolved inwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/10) to afford the title compound (46.9 mg, 9%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃) δ 8.87-8.86 (m, 1H), 8.19-8.18 (m, 1H),8.00-7.96 (m, 2H), 7.50-7.44 (m, 2H), 7.01-6.98 (d, J=15 Hz, 1H),5.27-5.10 (d, J=95 Hz, 1H), 4.69-4.63 (m, 1H), 4.35-4.16 (m, 3H),3.71-3.53 (m, 4H), 3.21-3.14 (m, 2H), 2.43-2.36 (m, 1H), 2.28-2.10 (m,1H), 2.01-1.97 (m, 2H), 1.79-1.72 (m, 2H).

Example 67 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[5-(trifluoromethyl)pyrazin-2-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: 2-(trifluoromethyl)-5-(trimethylstannyl)pyrazine (INT-67-1)

To a pressure tube was added 2-chloro-5-(trifluoromethyl)pyrazine (200mg, 1.1 mmol), hexamethylditin (0.281 mL 1.3 mmol), Pd(PPh₃)₄ (318.5 mg,0.27 mmol) and dioxane (10 mL). The reaction mixture was purged withNitrogen and heated at 100° C. for 1 hour. The resulting mixture wascooled to room temperature, and filtered through a thin layer of celite.The filter cake was washed with DCM. The filtrate was concentrated invacuo to give a dark solid. The crude was stored in the refrigerator andused without further purification. (341 mg, 100%). MS-ESI: [M+H]+311.9

Step 2: Following the HATU coupling procedure of Example 35, step 1:tert-butyl(2S,4R)-2-[(2-chloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(INT-67-3) (801 mg, 89%) was prepared from(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(450 mg, 1.9 mmol) and (2-chloro-4-pyridyl)methanamine hydrochloride(380 mg, 2.1 mmol), DIPEA (1 mL, 6.4 mmol), HATU (898 mg, 2.3 mmol), DMF(2 mL). MS-ESI: [M+H]+358.9 Step 3: Following the boc removal procedureof Example 35, step 3:(2S,4R)-N-[(2-chloro-4-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(INT-67-4) (375 mg, 100%) was prepared from tert-butyl(2S,4R)-2-[(2-chloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(500 mg, 1.94 mmol) and 4 N HCl in dioxane (3 mL, 12.4 mmol). MS-ESI:[M+H]+258.9 Step 4: Following the sulfonamide formation procedure ofExample 35, step 4 :(2S,4R)-N-[(2-chloro-4-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(INT-67-5) (95 mg, 63%) was prepared from(2S,4R)-N-[(2-chloro-4-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(INT-67-4) (100 mg, 0.3 mmol), Et3N (0.8 mL, 6 mmol),4-fluorobenzenesulfonyl chloride (70 mg, 0.36 mmol) in DCM (1 mL).MS-ESI: [M+H]+416.5 Step 5:(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl]pyrrolidine-2-carboxamide(67)

To a pressure tube was addedtrimethyl[5-(trifluoromethyl)pyrazin-2-yl]stannane (67 mg, 0.2 mmol),(2S,4R)-N-[(5-chloro-2-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(50 mg, 0.11 mmol), Pd(PPh₃)₄ (13 mg, 0.011 mmol) andN,N-dimethylacetamide (1 mL). The reaction mixture was purged withNitrogen and subject to microwave at 150° C. for 30 min. The resultingmixture was cooled to room temperature, and filtered through a thinlayer of celite. The crude was purified with reverse phase HPLC andafforded the title compound 67 (30 mg, 53%). MS-ESI: [M+H]+528.5

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J=2.1 Hz, 1H), 9.29 (d, J=1.3 Hz,1H), 8.81 (t, J=5.9 Hz, 1H), 8.73 (ddd, J=8.4, 2.3, 0.9 Hz, 1H), 8.17(d, J=1.3 Hz, 1H), 8.11-7.94 (m, 3H), 7.49-7.19 (m, 2H), 4.67-4.48 (m,2H), 4.39 (dd, J=17.4, 5.6 Hz, 1H), 2.24-2.10 (m, 1H), 2.02 (td, J=11.5,6.5 Hz, 1H), 1.84 (ddt, J=12.0, 6.1, 2.7 Hz, 1H), 1.71 (ddd, J=11.8,6.7, 2.9 Hz, 1H), 1.45 (s, 3H), 1.24 (s, 3H).

Example 68 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 55.

1H NMR (400 MHz, DMSO) δ 9.46-9.42 (s, 2H), 9.09-8.99 (t, J=6.0 Hz, 1H),8.04-7.94 (m, 2H), 7.79-7.72 (dt, J=9.9, 2.1 Hz, 1H), 7.72-7.67 (t,J=1.5 Hz, 1H), 7.54-7.45 (m, 2H), 7.38-7.30 (dt, J=9.6, 1.8 Hz, 1H),5.29-5.09 (m, 1H), 4.54-4.39 (m, 2H), 4.39-4.30 (d, J=24.6 Hz, 1H),3.73-3.61 (m, 1H), 3.21-3.11 (m, 1H), 2.22-2.02 (m, 2H)., LCMS (ESI)m/z:545.11 [M+H]+

Example 69 Preparation of(2S,4R)-N-[[4-(2,2-difluoro-6-azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate

A mixture of tert-butyl 4-methylidenepiperidine-1-carboxylate (1.00 g,5.07 mmol, 1.00 equiv), NaI (379.91 mg, 2.53 mmol, 0.50 equiv), andtrimethyl(trifluoromethyl)silane (1.80 g, 12.66 mmol, 2.50 equiv) in THF(10 mL) was stirred for 12 h at 60° C. under nitrogen. The reaction wasthen quenched by water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:10) to afford the title compound (1.2 g, 96%)as colorless oil.

Step 2: Preparation of 1,1-difluoro-6-azaspiro[2.5]octane hydrochloride

A mixture of tert-butyl 1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate(1.2 g, 4.85 mmol, 1.00 equiv) and HCl (saturated solution in 20 mL of1,4-dioxane) was stirred for 2 h at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (800mg, 90%) as a white solid.

Step 3: Preparation of(2S,4R)-N-[[4-(2,2-difluoro-6-azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-[(4-br-omo-5-fluoropyridin-2-yl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(135.00 mg, 0.28 mmol, 1.00 equiv), 1,1-difluoro-6-azaspiro[2.5]octanehydrochloride (51.83 mg, 0.28 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (58.43mg, 0.06 mmol, 0.20 equiv), XantPhos (65.33 mg, 0.11 mmol, 0.40 equiv),Cs₂CO₃ (275.90 mg, 0.85 mmol, 3.00 equiv), and toluene (5 mL) wasstirred for 12 h at 110° C. under nitrogen. The reaction was quenched bywater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (2:1). The crude product was re-purified by Prep-HPLC to affordthe title compound (26.5 mg, 17%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.15-8.13 (m, 1H), 7.89-7.86 (m, 2H), 7.54 (s,1H), 7.26-7.19 (m, 2H), 5.87 (d, J=57.2 Hz, 1H), 5.05 (d, J=52 Hz, 1H),4.66-4.60 (m, 1H), 4.37-4.43 (m, 1H), 4.29-4.25 (m, 1H), 3.88-3.64 (m,2H), 3.49-3.42 (m, 2H), 3.34-3.28 (m, 2H), 2.60-2.45 (m, 1H), 2.31-2.11(m, 1H), 1.79-1.74 (m, 4H), 1.16-1.12 (m, 2H).

Example 70 Preparation of(2S,4R)-N-((5-cyano-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-N-((5-cyano-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide

A mixture of methyl6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate(1.4 g, 2.66 mmol, 1.00 equiv) in tetrahydrofuran (20 mL)/water(2 mL)and LiOH (96 mg, 4.01 mmol, 1.50 equiv) in water (2 mL) was stirred for14 h at room temperature. The reaction was diluted with water and the pHvalue of the solution was adjusted to 7 with citric acid. The resultingsolution was extracted with dichloromethane and concentrated undervacuum. This resulted in the title compound (405 mg, 30%) as a yellowsolid.

Step 2: Preparation of tert-butyl(2S,4R)-2-[([5-carbamoyl-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylicacid (405 mg, 0.79 mmol, 1.00 equiv), NH₄Cl (51 mg, 0.95 mmol, 1.20equiv), HATU (361 mg, 0.95 mmol, 1.20 equiv), DIEA (307 mg, 2.38 mmol,3.00 equiv) in tetrahydrofuran (20 mL) was stirred for 14 h at roomtemperature. The reaction was quenched by water, extracted with ethylacetate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether(3:1) toafford the title compound (190 mg, 47%) as an off-white solid.

Step 3: Preparation of tert-butyl(2S,4R)-2-[([5-cyano-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4R)-2-[([5-carbamoyl-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(190 mg, 0.37 mmol, 1.00 equiv), TFAA (157 mg, 0.75 mmol, 2.00 equiv),and TEA (37 mg, 0.37 mmol, 1.00 equiv) in dichloromethane (5 mL) wasstirred for 30 seconds at room temperature. The reaction was thenquenched by water, extracted with dichloromethane, washed with brine,and concentrated under vacuum. This resulted in the crude product (200mg) as a yellow solid which was used for the next step without anyfurther purification.

Step 4: Preparation of(2S,4R)-N-([5-cyano-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-2-[([5-cyano-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(200 mg, 0.41 mmol, 1.00 equiv) and TFA (1 mL, 13.46 mmol, 33.20 equiv)in. dichloromethane (2 mL) was stirred for 2 min at room temperature.The reaction mixture was concentrated under vacuum. The residue wasdiluted with 2 mL of hydrogen chloride (6M) and concentrated undervacuum. The resulting solid washed with 2×20 mL of hexane to give thetitle compound as a crude product.

Step 5: Preparation of(2S,4R)-N-((5-cyano-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine -2-carboxamide

A mixture of 4-fluorobenzene-1-sulfonyl chloride (47.5 mg, 0.24 mmol,1.20 equiv),(2S,4R)-N-([5-cyano-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamide(80 mg, 0.10 mmol, 1.00 equiv, 50%), and TEA (62 mg, 0.61 mmol, 3.00equiv) in dichloromethane (5 mL) was stirred for 1 h at roomtemperature. The reaction was quenched by water, extracted withdichloromethane, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:1)to afford the title compound (15.8 mg, 28%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 7.88-7.85 (m, 2H), 7.81-7.77 (m,4H), 7.66-7.63 (m, 2H), 7.30-7.20 (m, 2H), 5.12-4.99 (d, J=51.2 Hz,1H),4.95-24.89 (dd, J=8.0 Hz, J=6.8 Hz, 1H), 4.67-4.61 (dd, J=4.8 Hz, J=5.2Hz, 1H), 4.30-4.25 (t, J=8.8 Hz, 1H), 3.93-3.84 (m, 1H), 3.75-3.64 (m,1H), 2.60-2.50 (m, 1H), 2.32-2.00 (m, 1H).

Example 71 Preparation of(2S,4R)-N-[[5-cyano-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of 6-chloro-4-iodopyridine-3-carboxylic acid

n-BuLi (8.8 mL, 2.5 M in hexanes, 2.00 equiv) was added dropwise into asolution of bis(propan-2-yl)amine (2.02 g, 19.96 mmol, 2.00 equiv) in 30mL of dry THF at −78° C. under nitrogen. The mixture was warmed to −30°C. and stirred for 30 min. A solution of 6-chloropyridine-3-carboxylicacid (1.58 g, 10.03 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) wasadded dropwise at −78° C. After 1 h 1₂ (3.07 g, 12.10 mmol, 1.20 equiv)was added at 0° C. After 30 minutes the reaction mixture was dilutedwith water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/1) to afford the title compound (1.2 g, 42%) as a yellow solid.

Step 2: Preparation of6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylic acid

A mixture of 6-chloro-4-iodopyridine-3-carboxylic acid (5 g, 17.64 mmol,1.00 equiv) in dioxane (100 mL),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (3.17 g, 16.60 mmol, 0.90equiv), potassium carbonate (6.9 g, 49.93 mmol, 2.80 equiv), Pd(dppf)Cl₂(1 g, 1.37 mmol), and water (20 mL) was stirred for 5 h at 80° C. undernitrogen. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/1). This resultedin the title compound (8.7 g) as a yellow solid.

Step 3: Preparation of methyl6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A mixture of6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylic acid(8.5 g, 28.09 mmol, 1.00 equiv) and thionyl chloride (10 mL, 137.85mmol, 4.90 equiv) in dichloromethane (50 mL) was stirred for 1 hour atroom temperature. The mixture was concentrated under vacuum and theresidue was dissolved in methanol (10 mL) and stirred for 30 min. Theresulting mixture was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/4) to afford the title compound (2.6 g, 29%) as a yellow solid.

Step 4: Preparation of methyl6-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A mixture of methyl6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate (1.0g, 3.16 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), Zn(CN)₂ (444mg, 3.78 mmol, 1.20 equiv), Pd₂(dba)₃ (200 mg, 0.22 mmol), and dppf (400mg, 0.72 mmol, 0.20 equiv) was stirred for 3 h at 100° C. undernitrogen. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/1) to afford thetitle compound (750 mg, 77%) as a yellow solid.

Step 5: Preparation of methyl6-(aminomethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylatehydrochloride

A mixture of methyl6-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate (750mg, 2.44 mmol, 1.00 equiv) in methanol (50 mL), conc. HCl (1 mL), andpalladium on carbon (750 mg, 7.05 mmol, 2.90 equiv) was stirred for 1 hat room temperature under hydrogen. The solids were filtered out and theliquid was concentrated under vacuum. This resulted in the titlecompound (700 mg, 92.3%) as a yellow solid.

Step 6: Preparation of methyl6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A mixture of methyl6-(aminomethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylatehydrochloride (700 mg, 2.25 mmol, 1.00 equiv) in tetrahydrofuran (50mL), (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylicacid (629 mg, 2.70 mmol, 1.20 equiv), HATU (1.28 g, 3.37 mmol, 1.50equiv), and DIPEA (870 mg, 6.73 mmol, 3.00 equiv) was stirred for 16 hat room temperature. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1/1)to afford the title compound (650 mg, 55%) as a yellow solid.

Step 7: Preparation of6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylicacid

A mixture of methyl6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate(600 mg, 1.14 mmol, 1.00 equiv) in tetrahydrofuran (20 mL), LiOH (96 mg,4.01 mmol, 3.50 equiv), and water (20 mL) was stirred for 16 h at roomtemperature. The pH value of the solution was adjusted to 5 with citricacid. The resulting solution was extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. This resulted in the titlecompound (480 mg, 82%) as a white solid.

Step 8: Preparation of tert-butyl(2S,4R)-2-[([5-carbamoyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of6-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylicacid (480 mg, 0.94 mmol, 1.00 equiv) in tetrahydrofuran (50 mL), NH₄Cl(496 mg, 9.27 mmol, 9.90 equiv), HATU (714 mg, 1.88 mmol, 2.00 equiv),and DIPEA (606 mg, 4.69 mmol, 5.00 equiv) was stirred for 16 h at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (450mg, 94%) as a white solid.

Step 9: Preparation of tert-butyl(2S,4R)-2-[([5-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of tert-butyl(2S,4R)-2-[([5-carbamoyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(450 mg, 0.88 mmol, 1.00 equiv) in dichloromethane (5 mL), TFAA (370 mg,1.76 mmol, 2.00 equiv), and TEA (133 mg, 1.31 mmol, 1.50 equiv) wasstirred for 30 min at room temperature. The reaction mixture was dilutedwith water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel chromatography eluting with petroleum ether/ethylacetate (2/1). This resulted in the title compound (410 mg, 94%) as ayellow solid.

Step 10: Preparation of(2S,4R)-N-([5-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-2-[([5-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(410 mg, 0.83 mmol, 1.00 equiv) and HCl (saturated solution in 50 mL of1,4-dioxane) was stirred for 3 h at room temperature. The resultingmixture was concentrated under vacuum. This resulted in the titlecompound (300 mg, 84%) as a yellow solid.

Step 11: Preparation of(2S,4R)-N-[[5-cyano-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-([5-cyano-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (300 mg, 0.70 mmol, 1.00 equiv) in dichloromethane (20mL), TEA (282 mg, 2.79 mmol, 4.00 equiv), and 4-fluorobenzene-1-sulfonylchloride (204 mg, 1.05 mmol, 1.50 equiv) was stirred for 16 h at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The crude product was purified by silicagel chromatography eluting with ethyl acetate/petroleum ether (1/1).This resulted in the title compound (41.1 mg, 11%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.17-9.04 (m, 3H), 8.43-8.40 (m, 1H), 8.15(d, J=8.1 Hz, 1H), 7.97-7.83 (m, 2H), 7.83 (s, 1H), 7.44 (t, J=9.0 Hz,2H), 5.28-5.10 (d, J=52.2 Hz, 1H), 4.60-4.58 (d, J=6.6 Hz, 2H),4.23-4.17(m, 1H), 3.71-3.63 (m, 2H), 2.73-2.08 (m, 2H).

Example 72 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 55.

1H NMR (400 MHz, DMSO) δ 9.15-9.10 (dt, J=2.0, 1.0 Hz, 1H), 9.11-9.04(t, J=6.0 Hz, 1H), 8.73-8.69 (dd, J=5.0, 0.9 Hz, 1H), 8.42-8.36 (m, 1H),8.36-8.29 (m, 1H), 8.07-8.01 (m, 2H), 8.01-7.95 (m, 2H), 7.52-7.43 (m,2H), 5.27-5.08 (m, 1H), 4.61-4.49 (m, 2H), 4.49-4.38 (d, J=24.1 Hz, 1H),3.73-3.60 (t, J=9.1 Hz, 1H), 3.25-3.14 (td, J=9.2, 7.0 Hz, 1H),2.30-2.06 (m, 2H)., LCMS (ESI) m/z:527.12 [M+H]+

Example 73: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.69-9.63 (s, 2H), 9.05-8.97 (t, J=6.0 Hz, 1H),8.78-8.72 (dd, J=5.1, 0.7 Hz, 1H), 8.20-8.16 (dd, J=1.5, 0.7 Hz, 1H),8.05-7.97 (m, 2H), 7.54-7.43 (m, 3H), 5.30-5.11 (d, J=52.3 Hz, 1H),4.59-4.40 (m, 2H), 4.25-4.15 (dd, J=10.0, 7.1 Hz, 1H), 3.79-3.59 (m,2H), 2.47-2.37 (m, 1H), 2.21-2.00 (m, 1H)., LCMS (ESI) m/z:528.11 [M+H]+

Example 74 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)-2-piperidyl]phenyl]methyl]pyrrolidine-2-carboxamide.

The reaction was carried out on the H-Cube with Rh/C 1.0 mL/min, 80 bar,100° C. in acetic acid. LCMS showed 50% of desired product. The reactionwas concentrated and purified by flash chromatography (EtOAc thenMeOH/DCM eluted at 8% MeOH). The product was submitted for rHPLC to give12.3 mg, 9.358% yield.

1H NMR (400 MHz, DMSO) δ 8.84-8.76 (t, J=6.0 Hz, 1H), 8.01-7.92 (m, 2H),7.51-7.40 (m, 2H), 7.20-7.14 (d, J=1.8 Hz, 1H), 7.12-6.96 (m, 2H),5.29-5.08 (d, J=52.6 Hz, 1H), 4.44-4.27 (m, 2H), 4.22-4.11 (m, 1H),3.79-3.55 (m, 3H), 3.05-2.84 (m, 2H), 2.46-2.28 (m, 2H), 2.17-1.94 (dt,J=43.0, 11.0 Hz, 1H), 1.86-1.63 (m, 4H)., LCMS (ESI) m/z:550.16 [M+H]+

Example 75: Preparation of(2S,4R)-N-[[3-[5-(difluoromethyl)-2-pyridyl]-5-fluoro-phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 8.95-8.84 (m, 2H), 8.22-8.15 (m, 1H), 8.13-8.06(m, 1H), 8.03-7.94 (m, 3H), 7.88-7.79 (ddd, J=10.1, 2.5, 1.5 Hz, 1H),7.52-7.41 (m, 2H), 7.35-7.04 (m, 2H), 5.31-5.10 (d, J=52.5 Hz, 1H),4.55-4.38 (m, 2H), 4.25-4.15 (dd, J=9.8, 7.2 Hz, 1H), 3.78-3.57 (m, 2H),2.47-2.28 (m, 1H), 2.20-1.98 (m, 1H)., LCMS (ESI) m/z:526.12 [M+H]+

Example 76: Preparation of(2S,4R)-N-([3-[6-(difluoromethoxy)pyridin-3-yl]-5-fluorophenyl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step1: Preparation of(2S,4R)-N-([3-[6-(difluoromethoxy)pyridin-3-yl]-5-fluorophenyl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-[(3-bromo-5-fluorophenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(150 mg, 0.31 mmol, 1.00 equiv) in dioxane (20 mL),2-(difluoromethoxy)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94mg, 0.35 mmol, 1.10 equiv), potassium carbonate (174 mg, 1.26 mmol, 4.00equiv) in water(4 mL), and Pd(dppf)Cl₂ (46 mg, 0.06 mmol, 0.20 equiv)was stirred for 6 h at 60° C. under nitrogen. The solids were filteredout. The liquid was diluted with ethyl acetate, washed with brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by Prep-HPLC to afford the title compound (47.4 mg, 28%) asa white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.21-8.18 (m, 1H), 8.00-7.97 (m,2H), 7.56 (s, 1H), 7.41 (s, 1H), 7.36-7.32 (m, 3H), 7.20-7.18 (m, 1H),7.05-7.03 (m, 1H), 5.21-5.10 (d, J=52 Hz, 1H), 4.55 (s, 2H), 4.28-4.23(m, 1H), 3.85-3.69 (m, 2H), 2.51-2.49 (m, 1H), 2.21-2.06 (m, 1H).

Example 77 Preparation of(2S,4R)-N-([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-(difluoromethoxy)-4-iodobenzene (1.35 g, 5.00 mmol, 1.00equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.413 g, 5.56 mmol, 1.10 equiv), AcOK (1.47 g, 14.98 mmol, 3.00 equiv),and Pd(dppf)Cl₂ (186 mg, 0.25 mmol, 0.05 equiv) in dioxane (30 mL)/water(3 mL) was stirred for 2 h at 95° C. under nitrogen. The mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:50) to afford thetitle compound (660 mg, 49%) as colorless oil.

Step 2: Preparation of2-chloro-4-[4-(difluoromethoxy)phenyl]-5-fluoropyridine

A mixture of2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(600 mg, 2.22 mmol, 1.00 equiv), 2-chloro-5-fluoro-4-iodopyridine (682.7mg, 2.65 mmol, 1.20 equiv), potassium carbonate (910 mg, 6.58 mmol, 3.00equiv), and Pd(dppf)Cl₂ (82.7 mg, 0.11 mmol, 0.05 equiv) in dioxane (20mL)/water(2 mL) was stirred for 12 h at 75° C. under nitrogen. Themixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:80).This resulted in the title compound (410 mg, 67%) as a white solid.

Step 3: Preparation of4-[4-(difluoromethoxy)phenyl]-5-fluoropyridine-2-carbonitrile

A mixture of 2-chloro-4-[4-(difluoromethoxy)phenyl]-5-fluoropyridine(370 mg, 1.35 mmol, 1.00 equiv), Zn(CN)₂ (208.7 mg, 1.78 mmol, 1.50equiv), dppf (65.8 mg, 0.12 mmol, 0.10 equiv), and Pd₂(dba)₃CHCl₃ (61.5mg, 0.06 mmol, 0.05 equiv) in N,N-dimethylformamide (10 ml) wasirradiated with microwave radiation for 2 h at 120° C. under nitrogen.The mixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:12) toafford the title compound (330 mg, 92%) as an off-white solid.

Step 4: Preparation of[4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methanaminehydrochloride

A mixture of4-[4-(difluoromethoxy)phenyl]-5-fluoropyridine-2-carbonitrile (300 mg,1.14 mmol, 1.00 equiv), concentrated hydrogen chloride (0.05 mL),palladium on carbon (600 mg) in methanol (30 mL) was stirred for 5 minat room temperature under hydrogen. The solids were filtered out and thefiltrate was concentrated under vacuum. This resulted in the titlecompound (310 mg) as a light yellow solid.

Step 5: Preparation of tert-butyl(2S,4R)-2-[([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(359 mg, 1.54 mmol, 1.33 equiv), HATU (643.7 mg, 1.69 mmol, 1.46 equiv),DIEA (595.9 mg, 4.61 mmol, 4.00 equiv), and[4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methanaminehydrochloride (310 mg, 1.16 mmol, 1.00 equiv) in N,N-dimethylformamide(15 mL) was stirred for 2 h at room temperature. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:3) to afford the title compound(310 mg, 55%) as orange oil.

Step 6: Preparation of(2S,4R)-N-([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-2-[([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate (310 mg, 0.64 mmol, 1.00 equiv), and saturated hydrogenchloride in dioxane (15 mL) was stirred for 12 h at room temperature.The reaction mixture was concentrated under vacuum to afford the titlecompound (255 mg, 95%) as a pink solid.

Step 7: Preparation of(2S,4R)-N-([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine -2-carboxamide

A mixture of 4-fluorobenzene-1-sulfonyl chloride (255 mg, 1.31 mmol,1.00 equiv),(2S,4R)-N-([4-[4-(difluoromethoxy)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (130.2 mg, 0.31 mmol, 1.10 equiv), TEA (184.8 mg, 1.83mmol, 3.00 equiv), and 4-dimethylaminopyridine (7.44 mg, 0.06 mmol, 0.10equiv) in dichloromethane (5 mL) was stirred for 2 h at roomtemperature. The mixture was diluted with water and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:4). This resulted in the title compound (108.2 mg, 15%) as anoff-white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.46 (s, 1H), 8.00-7.96 (m, 2H), 7.82-7.79 (m,3H), 7.36-7.22 (m, 3H), 7.16-6.67 (t, J=73.8 Hz, 1H), 5.22-5.05 (d,J=51.6 Hz, 1H), 4.60 (s, 1H), 4.29-4.23 (m, 1H), 3.84-3.66 (m, 2H),2.51-2.43 (m, 1H), 2.29-2.11 (m, 1H).

Example 78 Preparation of(2S,4R)-N-([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of methyl4-chloro-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate

A mixture of methyl 4,6-dichloropyridine-3-carboxylate (10 g, 48.54mmol, 2.00 equiv), [4-(trifluoromethyl)phenyl]boronic acid (4.6 g, 24.22mmol, 1.00 equiv), Pd(dppf)Cl₂ (800 mg, 1.09 mmol, 0.05 equiv), andpotassium carbonate (10 g, 72.36 mmol, 3.00 equiv) in 1,4-dioxane (100mL)/water (10 mL) was stirred for 3 h at 70° C. under nitrogen. Thereaction was then quenched by iced water, extracted with ethyl acetate,washed with brine, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:10) to afford the title compound (5.6 g , 73%) of as a whitesolid.

Step 2: Preparation of methyl4-cyano-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate

Into a 30-mL sealed tube was placed methyl4-chloro-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate (2 g, 6.34mmol, 1.00 equiv), Zn(CN)₂ (740 mg, 6.30 mmol, 1.00 equiv),Pd₂(dba)₃.CHCl₃ (320 mg, 0.31 mmol, 0.05 equiv), and dppf (350 mg, 0.63mmol, 0.10 equiv) in N,N-dimethylformamide (10 mL). The reaction mixturewas irradiated with microwave for 90 min at 110° C. The reaction wasthen quenched by water, extracted with ethyl acetate, washed with brine,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10) to afford thetitle compound (0.8 g , 41%) as a yellow solid.

Step 3: Preparation of methyl4-(aminomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylatehydrochloride

Into a 100-mL round-bottom flask was placed with methyl4-cyano-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate (150 mg,0.49 mmol, 1.00 equiv), palladium on carbon (10 mg), methanol (10 mL),and concentrated hydrogen chloride (0.1 mL). The resulting solution wasmaintained with an atmosphere of H₂ and stirred for 1 h at roomtemperature. The solids were filtered out and the solution wasconcentrated under vacuum to afford the title compound (147 mg, 87%) asa yellow solid.

Step 4: Preparation of methyl4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(67 mg, 0.29 mmol, 1.00 equiv), methyl4-(aminomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylatehydrochloride (100 mg, 0.29 mmol, 1.00 equiv), HATU (131 mg, 0.34 mmol,1.20 equiv), and DIEA (111 mg, 0.86 mmol, 3.00 equiv) in tetrahydrofuran(5 mL) was stirred for 14 h at room temperature. The reaction was thenquenched by water, extracted with ethyl acetate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (2:1) to afford the title compound (100 mg, 66%) as a white solid.

Step 5: Preparation of4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylicacid

LiOH (46 mg, 1.92 mmol, 2.00 equiv) in water (2 mL) was added dropwiseinto a stirred solution of methyl 4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate(500mg, 0.95 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 0° C. Afterbeing stirred for 14 h at room temperature the reaction was thenquenched by water and extracted with ethyl acetate. The aqueous layerswere combined and the pH value of the solution was adjusted to 7 withaqueous citric acid. The resulting solution was extracted with 2×100 mLof ethyl acetate and the organic layers were combined and concentratedunder vacuum. This resulted in to the title compound (396 mg, 81%) as ayellow solid.

Step 6: Preparation of tert-butyl(2S,4R)-2-[([5-carbamoyl-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylicacid (336 mg, 0.66 mmol, 1.00 equiv), NH₄Cl (42 mg, 0.79 mmol, 1.20equiv), HATU (299 mg, 0.79 mmol, 1.20 equiv), and DIEA (254 mg, 1.97mmol, 3.00 equiv) in tetrahydrofuran (10 mL) was stirred for 2.5 h atroom temperature. The reaction was then quenched by water, extractedwith ethyl acetate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (2:1) to afford the title compound (130 mg, 39%) as a yellowsolid.

Step 7: Preparation of tert-butyl(2S,4R)-2-[([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4R)-2-[([5-carbamoyl-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(130 mg, 0.25 mmol, 1.00 equiv), TFAA (107 mg, 0.51 mmol, 2.00 equiv),and TEA (38 mg, 0.38 mmol, 1.50 equiv) in dichloromethane (2 mL) wasstirred for 3 h at room temperature. The reaction was then quenched bywater, extracted with ethyl acetate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether. This resulted in the title compound (74 mg,59%) as a yellow solid.

Step 8: Preparation of(2S,4R)-N-([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2S,4R)-2-[([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(74 mg, 0.15 mmol, 1.00 equiv), and TFA (2 mL, 26.93 mmol, 179.20 equiv)in dichloromethane (4 mL) was stirred for 1 h at room temperature. Thereaction mixture was concentrated under vacuum. The residue was mixedwith 0.5 mL of hydrogen chloride (6M) and concentrated under vacuum.This resulted in the title compound (56 mg, 87%) as a white solid.

Step 9: Preparation of(2S,4R)-N-([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of 4-fluorobenzene-1-sulfonyl chloride (31 mg, 0.16 mmol, 1.20equiv),(2S,4R)-N-([5-cyano-2-[4-(trifluoromethyl)phenyl]pyridin-4-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (56 mg, 0.13 mmol, 1.00 equiv), and TEA (40 mg, 0.40 mmol,3.00 equiv) in dichloromethane (2 mL) was stirred for 14 h at roomtemperature. The reaction was then quenched by water, extracted withDCM, and concentrated under vacuum. The residue was purified by a silicagel column eluting with ethyl acetate/petroleum ether (1:1) to affordthe title compound (25.4 mg, 35%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.31-8.28 (d, J=8.4 Hz, 2H),8.15 (s, 1H), 7.92-7.88 (m, 2H), 7.73-7.70 (d, J=8.4 Hz, 2H), 7.50-7.46(m, 1H), 7.28-7.26 (d, J=6.6 Hz, 1H), 7.22 (s, 1H), 5.15-4.96 (m, 2H),4.68-4.57 (d, J=11.2 Hz, 1H), 4.34-4.28 (t, J=8.7 Hz, 1H), 3.97-3.61 (m,2H), 2.61-2.53 (m, 1H), 2.35-2.12 (m, 1H).

Example 79 Preparation of(2S,4R)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of methyl4-chloro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A mixture of methyl 4,6-dichloropyridine-3-carboxylate (5.5 g, 26.70mmol, 2.00 equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (2.5 g,13.09 mmol, 1.00 equiv), Pd(dppf)Cl₂ (480 mg, 0.66 mmol, 0.05 equiv),and potassium carbonate (5.5 g, 39.80 mmol, 3.00 equiv) in 1,4-dioxane(100 mL)/water (10 mL) was stirred for 3 h at 70° C. The reaction wasthen quenched by water, extracted with ethyl acetate, washed with brine,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3). This resultedin the title compound (2.0 g, 48%) as an off-white solid.

Step 2: Preparation of methyl4-cyano-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

Into a 30-mL sealed tube purged and maintained with an inert atmosphereof nitrogen was placed methyl4-chloro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate (400mg, 1.26 mmol, 1.00 equiv), Zn(CN)₂ (148 mg, 1.26 mmol, 1.00 equiv),Pd₂(dba)₃CHCl₃ (131 mg, 0.13 mmol, 0.10 equiv), and dppf (140 mg, 0.25mmol, 0.20 equiv) in N,N-dimethylformamide (8 mL). The reaction mixturewas irradiated with microwave for 90 min at 105° C. The reaction wasthen quenched by water, extracted with 2×50 mL of ethyl acetate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10). This resultedin the title compound (342 mg, 88%) as a yellow solid.

Step 3: Preparation of methyl4-(aminomethyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylatehydrochloride

A suspension of methyl4-cyano-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate (200mg, 0.65 mmol, 1.00 equiv), palladium on carbon (20 mg, 0.19 mmol, 0.30equiv) in methanol (10 mL)/concentrated aqueous HCl (0.3 mL).wasmaintained with an atmosphere of H₂ and stirred for 1 hour at roomtemperature. The solids were filtered out and the filtrate wasconcentrated under vacuum. The resulting mixture was washed with 20 mLof hexane to afford the title compound (224 mg, 99%) as a brown solid.

Step 4: Preparation of methyl4-([[(2R,4S)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(150 mg, 0.64 mmol, 1.00 equiv), methyl4-(aminomethyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylatehydrochloride (224 mg, 0.64 mmol, 1.00 equiv), HATU (294 mg, 0.77 mmol,1.20 equiv), and DIEA (249 mg, 1.93 mmol, 3.00 equiv) in tetrahydrofuran(10 mL) was stirred for 14 h at room temperature. The reaction was thenquenched by water, extracted with ethyl acetate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:10) to afford the title compound (212mg, 63%) as a yellow solid.

Step 5: Preparation of4-([[(2R,4S)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylicacid

A solution of LiOH (46 mg, 1.92 mmol, 2.00 equiv) in water(2 mL) wasadded dropwise into a solution of methyl4-([[(2R,4S)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate(500 mg, 0.95 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 0° C. Theresulting solution was stirred for 4 h at room temperature. The reactionwas diluted with 50 mL of water. The pH value of the solution wasadjusted to 7 with HCl (6M). The resulting solution was extracted withdichloromethane and the organic layers were combined and concentratedunder vacuum. This resulted in the title compound (191 mg) as a greensolid which was used for the next step without any further purification.

Step 6: Preparation of tert-butyl(2S,4R)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylicacid (191 mg, 0.37 mmol, 1.00 equiv), NH₄Cl (30 mg, 0.56 mmol, 1.50equiv), HATU (171 mg, 0.45 mmol, 1.20 equiv), and DIEA (145 mg, 1.12mmol, 3.00 equiv) in tetrahydrofuran (20 mL) was stirred for 14 h atroom temperature. The reaction was then quenched by 10 mL of water,extracted with ethyl acetate, dried over Na₂SO₄, and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (7:1). This resulted in 100 mg (52%) of thetitle compound as a yellow solid.

Step 7: Preparation of tert-butyl(2S,4R)-2-[([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4R)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(100 mg, 0.20 mmol, 1.00 equiv), TFAA (82 mg, 0.39 mmol, 2.00 equiv),and TEA (20 mg, 0.20 mmol, 1.00 equiv).in dichloromethane (5 mL) wasstirred for 14 h at room temperature. The reaction mixture wasconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1) to afford thetitle compound (100 mg) as a yellow solid

Step 8: Preparation of(2R,4R)-N-((5-cyano-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of (2R,4R)-tert-butyl2-((5-cyano-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate(74 mg, 0.15 mmol, 1.00 equiv) and TFA (2 mL, 26.93 mmol, 179.20 equiv)in dichloromethane (4 mL) was stirred for 1 h at room temperature. Thereaction mixture was concentrated under vacuum. The residue was dilutedwith 0.5 mL of HCl (6M). The resulting mixture was concentrated undervacuum to afford the title compound (56 mg, 87%) as a white solid

Step 9: Preparation of(2S,4R)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of 4-fluorobenzene-1-sulfonyl chloride (49 mg, 0.25 mmol,1.20 equiv),(2S,4R)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (91 mg, 0.21 mmol, 1.00 equiv), and TEA (64 mg, 0.63 mmol,3.00 equiv) in dichloromethane (3 mL) was stirred for 2 h at roomtemperature. The reaction was quenched by water, extracted withdichloromethane, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:1)to afford the title compound (15.9 mg, 14%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.51 (s, 1H), 8.97 (s, 1H), 8.70-8.68 (dd,J=1.6 Hz, J=1.6 Hz, 1H), 8.25 (s, 1H), 7.94-7.91 (m, 2H), 7.81-7.79 (d,J=8.4 Hz, 1H), 7.51-7.48 (m, 1H), 7.30-7.26 (m, 2H), 5.16-5.03 (m, 2H),4.64-4.58 (dd, J=4.8 Hz, J=4.8 Hz, 1H), 4.36-4.32 (m, 1H), 3.96-3.80 (m,1H), 2.66-2.64 (m, 1H), 2.15-2.35 (m, 1H).

Example 80 Preparation of(S)-54(4-fluorophenyl)sulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxamide.

Step 1: (5)-tert-butyl6-(((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)carbamoyl)-5-azaspirop.41heptane-5-carboxylate (INT-80-12)

To a solution of(5S)-6-tert-butoxycarbonyl-6-azaspiro[2.4]heptane-5-carboxylic acid (200mg, 0.83 mmol) and[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methanaminehydrochloride (265 mg, 0.91 mmol) in ethyl acetate (8.3 mL) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50 wt%) in ethyl acetate (0.74 mL, 1.24 mmol) and N,N-diisopropylethylamine(0.43 mL, 2.49 mmol) and the reaction mixture was stirred at roomtemperature overnight. An additional portion of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50 wt%) in ethyl acetate (1.48 mL, 2.48 mmol) was added and the reactionmixture was stirred for an additional 72 h. An additional portion of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50 wt%) in ethyl acetate (1.48 mL, 2.48 mmol) was added and the reactionmixture was heated to 60° C. The reaction mixture was quenched by theaddition of sat. aq. ammonium chloride and extracted with EtOAc (3×).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was adsorbedonto silica and purified by flash column chromatography with 0-100%EtOAc in Heptane to afford the desired compound as a brown foam (295 mg,76%).

MS-ESI: [M+H]+478.3

Step 2:(S)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxamide(INT-80-13)

To a solution of tert-butyl(5S)-5-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methylcarbamoyl]-6-azaspiro[2.4]heptane-6-carboxylate(295 mg, 0.62 mmol) in dichloromethane (4 mL) was added hydrochloricacid (4 mol/L) in 1,4-dioxane (2.0 mL, 8.0 mmol) and the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas concentrated in vacuo and used directly without furtherpurification.

MS-ESI: [M−HCl]+376.1

Step 3:(S)-5-((4-fluorophenyl)sulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxamide

To crude(S)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxamide(122 mg, 0.29 mmol) dissolved in dichloromethane (3 mL) was addedtriethylamine (0.123 mL, 0.88 mmol) and 4-fluorobenzenesulfonyl chloride(63 mg, 0.32 mmol) at room temperature for 4 h. The reaction mixture wasdiluted with DCM and water, the layers were separated and the aqueouslayer was extracted with DCM (2×). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was adsorbed onto silica and purified by flash columnchromatography with 0-10% MeOH in DCM to afford the partially purifiedtitle compound. The residue was purified by RP-HPLC to yield the titlecompound (110.6 mg, 70%) as a white solid.

MS-ESI: [M+H]+536.14

¹H NMR (400 MHz, DMSO) δ 9.49 (d, J=1.8 Hz, 1H), 9.30 (d, J=1.3 Hz, 1H),8.98 (t, J=6.1 Hz, 1H), 8.84-8.77 (m, 1H), 8.22 (d, J=1.3 Hz, 1H),8.14-8.08 (m, 1H), 8.08-8.01 (m, 2H), 7.58-7.46 (m, 2H), 4.67-4.56 (m,1H), 4.51-4.41 (m, 1H), 4.32-4.23 (m, 1H), 3.45 (d, J=10.4 Hz, 1H), 3.19(d, J=10.5 Hz, 1H), 1.93-1.78 (m, 2H), 0.62-0.52 (m, 1H), 0.52-0.41 (m,1H), 0.27-0.17 (m, 1H), 0.17-0.06 (m, 1H).

Example 81 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.24-9.15 (m, 1H), 9.05-8.96 (t, J=6.0 Hz, 1H),8.73-8.66 (dd, J=5.1, 0.8 Hz, 1H), 8.51-8.44 (m, 1H), 8.07-7.95 (m, 3H),7.89-7.84 (dd, J=1.8, 0.8 Hz, 1H), 7.82-7.75 (dd, J=5.2, 1.8 Hz, 1H),7.51-7.39 (m, 2H), 5.29-5.10 (m, 1H), 4.61-4.45 (m, 2H), 4.29-4.18 (dd,J=9.9, 7.1 Hz, 1H), 3.77-3.57 (m, 2H), 2.47-2.30 (m, 1H), 2.23-2.02(dddd, J=42.4, 13.8, 9.9, 3.4 Hz, 1H)., LCMS (ESI) m/z:527.12 [M+H]+

Example 82 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)pyrazin-2-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.53-9.51 (d, J=1.4 Hz, 1H), 9.33-9.30 (t,J=0.9 Hz, 1H), 9.06-8.98 (t, J=6.0 Hz, 1H), 8.79-8.74 (dd, J=5.2, 0.8Hz, 1H), 8.17-8.13 (dd, J=1.6, 0.8 Hz, 1H), 8.09-8.05 (dd, J=5.1, 1.7Hz, 1H), 8.03-7.96 (m, 2H), 7.49-7.39 (m, 2H), 5.31-5.12 (d, J=52.5 Hz,1H), 4.59-4.51 (d, J=5.9 Hz, 2H), 4.29-4.22 (dd, J=9.8, 7.2 Hz, 1H),3.75-3.57 (m, 2H), 2.47-2.31 (td, J=16.5, 16.0, 6.8 Hz, 1H), 2.24-2.02(dddd, J=42.1, 13.8, 9.6, 3.4 Hz, 1H)., LCMS (ESI) m/z:528.11 [M+H]+

Example 83 Preparation of(2S,4R)-N-[[2,6-bis[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.Step 1:(2S,4R)-N-((6,6″-bis(trifluoromethyl)-[3,2′:6′,3″-terpyridin]-4′-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

The title compound (60 mg, 98%) was prepared following the Bocdeprotection procedure of Example 2, Step 2 from tert-butyl(2S,4R)-2-[[2,6-bis[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(68 mg, 0.11 mmol) and 4M HCl in dioxane (4 ml) in DCM (4 ml). LCMS(ESI_Formic_MeCN): [H⁺]=514.

Step 2:(2S,4R)-N-[[2,6-bis[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

The title compound (48 mg, 65%) was prepared following the sulfonamidecoupling procedure of Example 2, Step 3 from(2S,4R)-N-[[2,6-bis[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-pyrrolidine-2-carboxamidehydrochloride (60 mg, 0.11 mmol), 4-fluorobenzenesulfonyl chloride (27mg, 0.14 mmol) and triethylamine (0.05 mL, 0.4 mmol) in DCM (6 mL).

1H NMR (400 MHz, DMSO-d₆) δ 9.58 (dt, J=2.2, 0.7 Hz, 2H), 9.11 (t, J=6.0Hz, 1H), 8.92-8.85 (m, 2H), 8.23 (d, J=0.8 Hz, 2H), 8.07 (dd, J=8.3, 0.8Hz, 2H), 8.05-8.00 (m, 2H), 7.51-7.44 (m, 2H), 5.22 (d, J=52.4 Hz, 1H),4.70-4.52 (m, 2H), 4.24 (dd, J=10.1, 7.1 Hz, 1H), 3.77-3.60 (m, 2H),2.44 (dd, J=17.2, 7.7 Hz, 2H), 2.24-2.03 (m, 1H).

Example 84 Preparation of(2S,4R)-N-[[2-chloro-6-[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.Step 1: (2S,4R)-tert-butyl2-(((2,6-dichloropyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

The title compound (1473 mg, 66%) was prepared following the amidecoupling procedure of Example 7, Step 7 from(2,6-dichloro-4-pyridyl)methanamine (1.00 g, 5.65 mmol),

(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(1320 mg, 5.66 mmol), HATU (2210 mg, 5.81 mmol) and triethylamine (2.05mL, 14.7 mmol) in DMF(12 mL). LCMS (ESI_Formic_MeCN): [MH⁺]=392.

Step 2: (2S,4R)-tert-butyl2-(((6-chloro-6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylateand (2S,4R)-tert-butyl2-(((6,6″-bis(trifluoromethyl)-[3,2′:6′,3″-terpyridin]-4′-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

The title compounds were prepared following the Suzuki couplingprocedure of Example 8, Step 1 from tert-butyl(2S,4R)-2-[(2,6-dichloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(157 mg, 0.40 mmol), [6-(trifluoromethyl)-3-pyridyl]boronic acid (105mg, 0.55 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg.,0.040 mmol) and 1 M aq Cs2CO3 (0.41 mL, 0.41 mmol, 1.0 mol/L) inacetonotrile (4 ml). Compound A (72 mg, 36%): LCMS (ESI_Formic_MeCN):[MH⁺]=503. Compound B (68 mg, 28%): LCMS (ESI_Formic_MeCN): [MH⁺]=614.

Step 3:(2S,4R)-N-((6-chloro-6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

The title compound (61 mg, 97%) was prepared following the Bocdeprotection procedure of Example 2, Step 2 from tert-butyl(2S,4R)-2-[[2-chloro-6-[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(72 mg, 0.1432 mmol) and 4M HCl in dioxane (5 mL) in DCM (5 ml). LCMS(ESI_Formic_MeCN): [MH⁺]=403.

Step 4:(2S,4R)-N-[[2-chloro-6-[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

The title compound (47 mg, 61%) was prepared following the sulfonamidecoupling procedure of Example 2, Step 3 from(2S,4R)-N-[[2-chloro-6-[6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-pyrrolidine-2-carboxamidehydrochloride (61 mg, 0.14 mmol), 4-fluorobenzenesulfonyl chloride (33mg, 0.17 mmol) and triethylamine (0.35 mL, 2.5 mmol) in DCM (5 ml).

1H NMR (400 MHz, DMSO-d₆) δ 9.38 (d, J=2.2 Hz, 1H), 9.03 (t, J=6.0 Hz,1H), 8.71-8.64 (m, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.05 (dd, J=8.3, 0.8 Hz,1H), 8.03-7.97 (m, 2H), 7.60 (d, J=1.1 Hz, 1H), 7.51-7.43 (m, 2H), 5.20(d, J=52.6 Hz, 1H), 4.60-4.41 (m, 2H), 4.23-4.14 (m, 1H), 3.79-3.57 (m,2H), 2.49-2.36 (m, 1H), 2.23-1.98 (m, 1H).

Example 85 Preparation of(2S,4R)-4-fluoro-N-[[3-fluoro-5-[2-oxo-4-(trifluoromethyl)-1-pyridyl]phenyl]methyl]-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure ofExample 86.

¹H NMR (400 MHz, DMSO) δ 8.93-8.86 (t, J=6.0 Hz, 1H), 7.99-7.92 (m, 2H),7.92-7.87 (dt, J=7.2, 0.9 Hz, 1H), 7.50-7.41 (m, 2H), 7.37-7.25 (m, 3H),6.94-6.89 (dq, J=2.0, 1.0 Hz, 1H), 6.56-6.51 (dd, J=7.2, 2.0 Hz, 1H),5.28-5.09 (m, 1H), 4.50-4.33 (m, 2H), 4.21-4.11 (dd, J=9.9, 7.1 Hz, 1H),3.73-3.54 (m, 2H), 2.44-2.30 (td, J=15.2, 14.7, 6.1 Hz, 1H), 2.19-1.96(m, 1H)., LCMS (ESI) m/z:560.11 [M+H]+

Example 86 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

A solution containing(2S,4R)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(80 mg, 0.1676 mmol), 4-(trifluoromethyl)-1h-pyrazole (48.0 mg, 0.3352mmol), cuprous iodide (31.92 mg, 0.1676 mmol),N,N′-dimethylethylenediamine (0.036 mL, 0.34 mmol) and potassiumcarbonate (48.65 mg, 0.3520 mmol) in 1,4-dioxane (1.7 mL) was stirred at100° C. 18 h. The crude was filtered thru celite and purified by flashchromatography (EtOAc/Fleptane_eluted at 80% EtOAc) then submitted forrHPLC to give 60.9 mg, 68.23% yield.

1H NMR (400 MHz, DMSO) δ 9.19-9.14 (t, J=1.0 Hz, 1H), 8.95-8.88 (t,J=6.1 Hz, 1H), 8.28-8.22 (d, J=0.8 Hz, 1H), 8.02-7.93 (m, 2H), 7.77-7.72(t, J=1.7 Hz, 1H), 7.71-7.65 (dt, J=10.0, 2.2 Hz, 1H), 7.51-7.42 (m,2H), 7.25-7.18 (ddd, J=9.5, 2.4, 1.3 Hz, 1H), 5.30-5.10 (m, 1H),4.53-4.36 (m, 2H), 4.22-4.13 (dd, J=9.9, 7.1 Hz, 1H), 3.74-3.56 (m, 2H),2.45-2.31 (m, 1H), 2.20-1.97 (m, 1H)., LCMS (ESI) m/z:533.11 [M+H]+

Example 87 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 86.

1H NMR (400 MHz, DMSO) δ 8.95-8.89 (t, J=6.1 Hz, 1H), 8.75-8.71 (dq,J=2.7, 1.0 Hz, 1H), 8.02-7.94 (m, 2H), 7.74-7.65 (m, 2H), 7.50-7.41 (m,2H), 7.28-7.19 (ddd, J=9.6, 2.3, 1.4 Hz, 1H), 7.10-7.07 (m, 1H),5.30-5.08 (d, J=52.4 Hz, 1H), 4.53-4.36 (m, 2H), 4.22-4.13 (dd, J=9.8,7.2 Hz, 1H), 3.75-3.57 (m, 2H), 2.46-2.29 (td, J=16.3, 7.2 Hz, 1H),2.18-1.98 (m, 1H)., LCMS (ESI) m/z:533.11 [M+H]+

Example 88 Preparation of(2S,4R)-N-[[4-[4-(difluoromethyl)phenyl]-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of 4-(2-chloro-5-fluoropyridin-4-yl)benzaldehyde

A mixture of (4-formylphenyl)boronic acid (500 mg, 3.33 mmol, 1.00equiv), 2-chloro-5-fluoro-4-iodopyridine (575 mg, 2.23 mmol, 0.70equiv), Pd(dppf)Cl₂ (80 mg, 0.11 mmol), potassium carbonate (930 mg,6.73 mmol, 2.00 equiv), and 1,4-dioxane (15 mL)/water(1.5 mL) wasstirred for 12 h at 75° C. under nitrogen. The reaction mixture wasdiluted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with petroleum ether/ethyl acetate (5:1).This resulted in the title compound (520 mg, 66%) as an off-white solid.

Step 2: Preparation of2-chloro-4-[4-(difluoromethyl)phenyl]-5-fluoropyridine

DAST (3.56 g, 22.09 mmol, 10.00 equiv) was added dropwise into a mixtureof 4-(2-chloro-5-fluoropyridin-4-yl)benzaldehyde (520 mg, 2.21 mmol,1.00 equiv) in dichloromethane (130 mL) at −78° C. under nitrogen. Theresulting solution was stirred for 12 h at room temperature. Thereaction was then quenched by water, extracted with ethyl acetate,washed with saturated solution of sodium bicarbonate and then brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with petroleumether/ethyl acetate (5:1) to afford the title compound (500 mg, 88%) asa white solid.

Step 3: Preparation of4-[4-(difluoromethyl)phenyl]-5-fluoropyridine-2-carbonitrile

A mixture of 2-chloro-4-[4-(difluoromethyl)phenyl]-5-fluoropyridine (500mg, 1.94 mmol, 1.00 equiv), Zn(CN)₂ (272 mg, 2.32 mmol, 1.20 equiv),Pd₂(dba)₃CHCl₃ (200 mg, 0.19 mmol, 0.10 equiv), and dppf (214 mg, 0.39mmol, 0.20 equiv) in N,N-dimethylformamide (16 mL) was stirred for 1.5 hat 100° C. under nitrogen. The residue was diluted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith petroleum ether/ethyl acetate (10:1). This resulted in the titlecompound (440 mg, 91%) as a light yellow solid.

Step 4: Preparation of[4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methanamine

A mixture of4-[4-(difluoromethyl)phenyl]-5-fluoropyridine-2-carbonitrile (440 mg,1.77 mmol, 1.00 equiv), methanol (40 mL), and palladium on carbon (400mg, 3.76 mmol, 2.10 equiv) was stirred for 2 h at room temperature underhydrogen. The solids were filtered out and the liquid was concentratedunder vacuum. This resulted in the title compound (420 mg, 94%) as anoff-white solid.

Step 5: Preparation of tert-butyl(2S,4R)-2-[([4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(92 mg, 0.39 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), DIEA (154mg, 1.19 mmol, 3.00 equiv), HATU (226 mg, 0.59 mmol, 1.50 equiv), and[4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methanamine (100 mg,0.40 mmol, 1.00 equiv) was stirred for 12 h at room temperature. Thereaction mixture was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with petroleumether/ethyl acetate (5:1). This resulted in the title compound (120 mg,65%) as an off-white solid.

Step 6: Preparation of(2S,4R)-N-([4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-2-[([4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(138 mg, 0.30 mmol, 1.00 equiv) and HCl (saturated solution in 5 ml ofdioxane) was stirred for 1 h at room temperature. The resulting mixturewas concentrated under vacuum to afford the title compound (120 mg,crude) as an off-white solid.

Step 7: Preparation of(2S,4R)-N-[[4-[4-(difluoromethyl)phenyl]-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-([4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (120 mg, 0.33 mmol, 1.00 equiv), dichloromethane (10 mL),TEA (99 mg, 0.98 mmol, 3.00 equiv), and 4-fluorobenzene-1-sulfonylchloride (64 mg, 0.33 mmol, 1.00 equiv) was stirred for 2 h at roomtemperature. The reaction mixture was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withpetroleum ether/ethyl acetate (1:2) to afford the title compound (41.4mg, 24%) as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.01-8.99 (m, 1H), 8.64 (s, 1H), 8.00-7.98 (m,2H), 7.98-7.97 (m, 2H), 7.81-7.70 (m, 3H), 7.69-7.67 (m, 2H), 7.48-7.43(m, 3H), 5.28-5.10 (d, J=27 Hz, 1H), 4.50-4.46 (m, 2H), 4.20-4.17 (m,1H), 3.72-3.59 (m, 2H), 2.46-2.35 (m, 1H), 2.27-2.02 (m, 1H).

Example 89 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[6-(trifluoromethyl)pyridazin-3-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

The title compound was prepared using the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 8.97-8.90 (t, J=6.0 Hz, 1H), 8.59-8.55 (m, 1H),8.41-8.37 (d, J=9.0 Hz, 1H), 8.09-8.04 (t, J=1.5 Hz, 1H), 8.01-7.94 (m,3H), 7.50-7.39 (m, 3H), 5.29-5.10 (d, J=52.4 Hz, 1H), 4.57-4.42 (m, 2H),4.22-4.14 (dd, J=9.9, 7.1 Hz, 1H), 3.74-3.58 (m, 2H), 2.44-2.30 (m, 1H),2.20-1.98 (m, 1H)., LCMS (ESI) m/z:545.2 [M+H]+

Example 90 Preparation of(2S,4R)-N-[[3-[5-(difluoromethyl)pyrazin-2-yl]-5-fluoro-phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

The title compound was prepared using the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 9.43-9.40 (d, J=1.4 Hz, 1H), 9.06-9.02 (d,J=1.3 Hz, 1H), 8.96-8.89 (t, J=6.1 Hz, 1H), 8.06-8.02 (t, J=1.5 Hz, 1H),8.01-7.95 (m, 2H), 7.95-7.88 (dt, J=9.8, 2.0 Hz, 1H), 7.51-7.42 (m, 2H),7.40-7.33 (dd, J=9.7, 2.1 Hz, 1H), 7.32-7.03 (t, J=54.2 Hz, 1H),5.30-5.09 (d, J=52.4 Hz, 1H), 4.55-4.40 (m, 2H), 4.24-4.14 (dd, J=9.8,7.2 Hz, 1H), 3.76-3.71 (q, J=2.0, 1.5 Hz, 1H), 3.70-3.57 (m, 1H),2.43-2.29 (dt, J=16.5, 7.9 Hz, 1H), 2.20-1.98 (m, 1H)., LCMS (ESI)m/z:527.2 [M+H]+

Example 91 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

(2S,4R)-tert-butyl2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

To a solution of(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (A,2000 mg, 8.6 mmol) and (3-bromo-5-fluoro-phenyl)methanamine (1.9 g, 9.4mmol) in N,N-dimethylformamide (34 ml) was addedN,N-diisopropylethylamine (2.2 mL, 13 mmol) and HATU (4.0 g, 10 mmol).The reaction mixture was stirred at RT 2 h.The reaction was quenchedwith water and extracted with EtOAc. The organic layers was dried withsodium sulfate, filtered, and concentrated via rotovap. The crudeproduct was purified by flash chromatography (EtOAc/Heptane_eluted at50% EtOAc) to give 3.24 g, 90% yield. LCMS (ESI) m/z:419.1 [M+H]+

(2S ,4R)-N-(3-bromo-5-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-2-[(3-bromo-5-fluoro-phenyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(820 mg, 1.956 mmol) in 1,4-dioxane (6.519 mL) was added hydrochloricacid (4 mol/L) in 1,4-dioxane (4.9 mL, 19.56 mmol). The reaction mixturewas stirred at RT 6 h. The reaction was concentrated and carried to nextstep. LCMS (ESI) m/z:318.9 [M+H]+

(2 S,4R)-N-(3-bromo-5-fluorobenzyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(624 mg, 1.9553 mmol) in dichloromethane (39 mL) was added triethylamine(5.45 mL, 39.11 mmol) then 4-fluorobenzenesulfonyl chloride (571.0 mg,2.933 mmol). The reaction was stirred at RT 2 h. The reaction wasquenched with water and extracted with EtOAc. The organic layers wasdried with sodium sulfate, filtered, and concentrated via rotovap. Thecrude product was purified by flash chromatography (EtOAc/Heptane_elutedat 65% EtOAc) to give 933.4 mg, 89.46% yield. LCMS (ESI) m/z:477.0[M+H]+

(2S,4R)-4-fluoro-N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(205 mg, 0.4295 mmol) and bis(pinacolato)diboron (166.9 mg, 0.6442 mmol)in 1,4-dioxane (8.60 mL, 100.6 mmol) was added potassium acetate (126.5mg, 0.0805 mL, 1.288 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.74 mg,0.04295 mmol). The reaction mixture was degassed then heated 85° C. 18h. The reaction was filtered thru celite. The crude was concentrated andcarried to next step. LCMS (ESI) m/z:525.1 [M+H]+

(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide(225 mg, 0.4291 mmol), 5-bromo-2-(trifluoromethyl)pyrimidine (153.9 mg,0.6442 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.74 mg,0.04295 mmol) and cesium carbonate (279.9 mg, 0.8590 mmol) in water (2.0mL) and acetonitrile (4.0 mL) was degassed. The reaction mixture washeated at 95° C. for 2 h. The reaction was filtered thru celite. Thecrude product was purified by flash chromatography (EtOAc/Hep_eluted at70% EtOAc) then submitted for rHPLC to give 111.2 mg, 47.55% yield.

1H NMR (400 MHz, DMSO) δ 9.46-9.37 (s, 2H), 8.98-8.89 (t, J=6.0 Hz, 1H),8.03-7.94 (m, 2H), 7.77-7.70 (m, 2H), 7.51-7.42 (m, 2H), 7.40-7.31 (m,1H), 5.31-5.09 (m, 1H), 4.56-4.37 (m, 2H), 4.23-4.13 (dd, J=9.9, 7.1 Hz,1H), 3.77-3.55 (m, 2H), 2.47-2.29 (m, 1H), 2.20-1.98 (m, 1H)., LCMS(ESI) m/z:545.2 [M+H]+

Example 92 Preparation of(2S,4R)-N-[[6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidin-4-yl]methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 5-bromo-2,2-difluoro-2H-1,3-benzodioxole (1 g, 4.22 mmol,1.00 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.2 g, 4.73 mmol, 1.10 equiv), Pd(dppf)Cl₂ (300 mg, 0.41 mmol, 0.10equiv), and AcOK (800 mg, 8.15 mmol, 2.00 equiv) in dioxane (20 mL) wasstirred overnight at 100° C. The reaction mixture was concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:20) to afford the title compound (900mg, 75%) as yellow oil.

Step 2: Preparation of4-chloro-6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidine

A solution of2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(800 mg, 2.82 mmol, 1.00 equiv), 4,6-dichloropyrimidine (640 mg, 4.30mmol, 1.50 equiv), potassium carbonate (776 mg, 5.61 mmol, 2.00 equiv),and Pd(PPh₃)₄ (328 mg, 0.28 mmol, 0.10 equiv) in dioxane (15 mL)/water(3 mL) was stirred overnight at 100° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:6) to afford thetitle compound (570 mg, 75%) as a white solid.

Step 3: Preparation of6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidine-4-carbonitrile

A solution of4-chloro-6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidine (500 mg,1.85 mmol, 1.00 equiv), Pd(PPh₃)₄ (180 mg, 0.16 mmol, 0.10 equiv), andZn(CN)₂ (330 mg, 2.81 mmol, 1.50 equiv) in N,N-dimethylformamide (8 mL)was stirred for 1 h at 100° C. The reaction mixture was diluted with 100ml of ethyl acetate, washed with water, dried over sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:6). This resultedin the title compound (360 mg, 75%) as a white solid.

Step 4: Preparation of[6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidin-4-yl]methanamine

A mixture of6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidine-4-carbonitrile (340mg, 1.30 mmol, 1.00 equiv), palladium on carbon (100 mg, 0.94 mmol, 1.00equiv), and hydrogen chloride (2 drop) in methanol (80 mL) was stirredfor 5 min at room temperature under hydrogen. The solids were filteredout and the liquid was concentrated under vacuum. The residue waspurified by a silica gel column eluting with DCM:MeOH (100:5) to affordthe title compound (220 mg, 64%) as a white solid.

Step 5: Preparation of(2S,4R)-N-[[6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidin-4-yl]methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (110 mg, 0.38 mmol, 1.0 equiv), HATU (172 mg, 0.45 mmol, 1.2equiv), and DIEA (200 mg, 1.55 mmol, 2.00 equiv) inN,N-dimethylformamide (10 mL) was stirred for 10 min at roomtemperature. Then[6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyrimidin-4-yl]methanamine (100mg, 0.38 mmol, 1.0 equiv) was added and the resulting solution wasstirred for an additional 3 h at room temperature. The resultingsolution was diluted with ethyl acetate, washed with water, dried oversodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate to afford the titlecompound (43.2 mg, 21%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.06-8.02 (m, 3H), 7.96-7.92 (m,2H), 7.80 (s, 1H), 7.28-7.23 (m, 2H),7.18 (d, J=8.4 Hz, 1H), 5.15-5.02(d, J=51.2 Hz, 1H), 4.95-4.92 (m, 1H), 4.66-4.62 (m, 1H), 4.29 (t, J=8.4Hz, 1H), 3.88-3.72 (m, 2H), 2.59-2.53 (m, 1H), 2.34-2.17 (m, 1H).

Example 93 Preparation of(2R,3S)-3-fluoro-N-((6-(3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of (2S,3R)-tert-butyl2-((6-(3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methylcarbamoyl)-3-hydroxypyrrolidine-1-carboxylate

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(209 mg, 0.90 mmol, 1.00 equiv),[6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanaminehydrochloride (280 mg, 0.91 mmol, 1.00 equiv), HATU (414 mg, 1.09 mmol,1.20 equiv), and DIEA (351 mg, 2.72 mmol, 3.00 equiv) in tetrahydrofuran(10 mL) was stirred for 6 h at room temperature. The reaction was thenquenched by water. The resulting solution was extracted with 2×50 mL ofethyl acetate and the organic layers were combined and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (2:1). This resulted in the titlecompound (270 mg, 62%) as an off-white solid.

Step 2: Preparation of (2R,3S)-tert-butyl3-fluoro-2-((6-(3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidine-1-carboxylate

DAST (36.6 mg, 0.23 mmol, 2.20 equiv) was added slowly into a solutionof tert-butyl(2S,3R)-2-[([6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate(50 mg, 0.10 mmol, 1.00 equiv) in dichloromethane (5 mL) at 0° C. undernitrogen. The resulting solution was stirred for 10 min at 0° C. in awater/ice bath. The reaction was then quenched by iced water, extractedwith 2×50 mL of dichloromethane, washed with 2×10 mL of saturatedaqueous NaHCO₃, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether(3:1)to afford the title compound 57 mg (crude) as a brown solid

Step 3: Preparation of(2R,3S)-3-fluoro-N-((6-(3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2R,3S)-3-fluoro-2-[([6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(57 mg, 0.12 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (5 mL) was stirred for 14 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in thetitle compound (44 mg, 89%) as a brown solid.

Step 4: Preparation of(2R,3S)-3-fluoro-N-((6-(3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine -2-carboxamide

A mixture of 4-fluorobenzene-1-sulfonyl chloride (24 mg, 0.12 mmol, 1.20equiv),(2R,3S)-3-fluoro-N-([6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (44 mg, 0.10 mmol, 1.00 equiv), and TEA (31.5 mg, 0.31mmol, 3.00 equiv) in dichloromethane (5 mL) was stirred for 14 h at roomtemperature. The reaction mixture was quenched by water, extracted byethyl acetate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (3:1)to afford the title compound (21.4 mg, 38%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.10-8.06 (t, J=8.5 Hz, 2H),7.94-7.91 (m, 3H), 7.78-7.72 (m, 2H), 7.31-7.26 (m, 2H), 5.38-5.25 (d,J=50.8 Hz, 1H), 4.93-4.91 (m, 1H), 4.58-4.53 (m, 1H), 4.43-4.37 (d,J=22.0 Hz,1H), 3.83 (t, J=8.8 Hz, 1H), 3.35-3.28 (m, 1H), 2.23-2.03 (m,2H).

Example 94 Preparation of(2S,4R)-N-[[3-[6-(difluoromethyl)-3-pyridyl]-5-fluoro-phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.07-9.04 (dd, J=2.3, 0.8 Hz, 1H), 8.93-8.87(t, J=6.0 Hz, 1H), 8.35-8.30 (dd, J=8.2, 2.3 Hz, 1H), 8.02-7.94 (m, 2H),7.80-7.75 (m, 1H), 7.65-7.62 (t, J=1.5 Hz, 1H), 7.62-7.56 (ddd, J=10.0,2.5, 1.6 Hz, 1H), 7.50-7.41 (m, 2H), 7.30-7.23 (ddd, J=9.8, 2.4, 1.5 Hz,1H), 7.17-6.86 (t, J=54.9 Hz, 1H), 5.30-5.10 (d, J=52.7 Hz, 1H),4.54-4.37 (m, 2H), 4.23-4.13 (dd, J=9.9, 7.1 Hz, 1H), 3.76-3.56 (m, 2H),2.46-2.30 (m, 1H), 2.20-1.99 (m, 1H)., LCMS (ESI) m/z:526.12 [M+H]+

Example 95 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 9.09-9.03 (dt, J=1.9, 0.9 Hz, 1H), 8.95-8.87(t, J=6.0 Hz, 1H), 8.35-8.29 (m, 1H), 8.28-8.23 (m, 1H), 8.03-7.93 (m,3H), 7.91-7.83 (ddd, J=10.2, 2.6, 1.6 Hz, 1H), 7.51-7.41 (m, 2H),7.36-7.28 (ddd, J=9.5, 2.4, 1.3 Hz, 1H), 5.31-5.10 (d, J=52.5 Hz, 1H),4.54-4.39 (m, 2H), 4.23-4.13 (dd, J=9.8, 7.1 Hz, 1H), 3.79-3.57 (m, 2H),2.46-2.29 (td, J=16.5, 15.8, 7.1 Hz, 1H), 2.19-1.98 (m, 1H)., LCMS (ESI)m/z:544.11 [M+H]+

Example 96 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-methyl-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile(1.08 g, 3.81 mmol, 1.00 equiv) in dioxane (50 mL), Pd(dppf)Cl₂ (560 mg,0.77 mmol, 0.20 equiv), and Zn(CH₃)₂ (4.2 mL, 5.72 mmol, 1.30 equiv) wasstirred for overnight at 65° C. under nitrogen. The resulting mixturewas concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (15:100). Thisresulted in the title compound (292 mg, 29%) as yellow oil.

Step 2: Preparation of[5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile (280mg, 1.06 mmol, 1.00 equiv) in methanol (40 mL), palladium on carbon (50mg, 0.47 mmol, 0.40 equiv), and concentrated hydrogen chloride (1 mL)was stirred for 10 min at room temperature under hydrogen. The solidswere filtered out and the liquid was concentrated under vacuum. Thisresulted in the title compound (263 mg, 81%) as an off-white solid.

Step 3: Preparation of tert-butyl(2S,4R)-4-fluoro-2-[([5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of[5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride (260 mg, 0.86 mmol, 1.00 equiv) in N,N-dimethylformamide(20 mL),(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(200 mg, 0.86 mmol, 1.00 equiv), DIEA (1.11 g, 8.59 mmol, 10.00 equiv),and HATU (392 mg, 1.03 mmol, 1.20 equiv) was stirred for 2 h at roomtemperature. The reaction was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with dichloromethane/methanol (100:5) to afford the titlecompound (380 mg, 92%) as brown oil.

Step 4: Preparation of2S,4R)-4-fluoro-N-([5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2S,4R)-4-fluoro-2-[([5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(380 mg, 0.79 mmol, 1.00 equiv) in HCl (saturated solution in 50 mL of1,4-dioxane) was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (285mg, 86%) as a light brown solid.

Step 5: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-methyl-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-N-([5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (285 mg, 0.680 mmol, 1.000 equiv) in dichloromethane (20mL), TEA (687 mg, 6.789 mmol, 10.000 equiv), and4-fluorobenzene-1-sulfonyl chloride (200 mg, 1.028 mmol, 1.500 equiv)was stirred for 2 h at room temperature. The resulting solution wasdiluted with dichloromethane, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with dichloromethane/methanol (100:10).This resulted in the title compound (71.6 mg, 19%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.92-8.83 (m, 2H), 8.52 (s, 1H), 8.18-8.16 (m,1H), 8.01-7.91 (m, 3H), 7.45-7.40 (m, 3H), 5.27-5.01 (d, J=52.2 Hz, 1H),4.47-4.44 (m, 2H), 4.23-4.17 (m, 1H), 3.67-3.57 (m, 2H), 2.44-2.41 (m,1H), 2.38-2.14 (m, 3H), 2.07-2.00 (m, 1H).

Example 97 Preparation of(2R,3S)-3-fluoro-N-([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of4-fluoro-3-(5-(trifluoromethyl)pyrazin-2-yl)benzonitrile

A mixture of (5-cyano-2-fluorophenyl)boronic acid (91 mg, 0.55 mmol,1.00 equiv), 2-chloro-5-(trifluoromethyl)pyrazine (100 mg, 0.55 mmol,1.00 equiv), Pd(PPh₃)₄ (63 mg, 0.05 mmol, 0.10 equiv), and potassiumcarbonate (152 mg, 1.10 mmol, 2.00 equiv) in 1,4-dioxane (2mL)/water(0.4 mL) was stirred overnight at 95° C. under nitrogen. Thereaction mixture was diluted with water, extracted with ethyl acetate,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:10). This resulted in the title compound (110mg) as a light yellow solid

Step 2: Preparation of[4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanamine

A mixture of 4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]benzonitrile(200 mg, 0.75 mmol, 1.0 equiv), palladium on carbon (50 mg, 0.47 mmol,1.00 equiv), and HCl (conc.)(1drop) in methanol (20 mL) was stirred for20 min at room temperature under hydrogen. The solids were filtered outand the liquid was concentrated under vacuum. This resulted in the titlecompound (95 mg, 47%) as a brown solid.

Step 3: Preparation oftert-butyl(2S,3R)-2-[([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(90 mg, 0.39 mmol, 1.00 equiv), DIEA (226 mg, 1.75 mmol, 2.00 equiv),and HATU (160 mg, 0.42 mmol, 1.20 equiv) in N,N-dimethylformamide (5 mL)was stirred for 10 min at room temperature. Then[4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanamine (95 mg,0.35 mmol, 1.00 equiv) was added to the reaction mixture. The resultingsolution was stirred overnight at room temperature. The reactionsolution was diluted with water, extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (160 mg, 85%) as a light yellow solid.

Step 4: Preparation of tert-butyl(2R,3S)-3-fluoro-2-[([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (220 mg, 1.36 mmol, 3.00 equiv) was added dropwise into a stirredsolution of tert-butyl(2S,3R)-2-[([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate(220 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (20 mL) at 0° C. Theresulting solution was stirred for 5 h at room temperature and quenchedby aqueous NaHCO₃. The reaction solution was extracted with 100 mL ofethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1) to afford the title compound(65 mg, 29%) as colorless oil.

Step 5: Preparation of(2R,3S)-3-fluoro-N-([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)pyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2R,3S)-3-fluoro-2-[([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]pyrrolidine-1-carboxylate(65 mg, 0.13 mmol, 1.00 equiv) and saturated hydrogen chloride indioxane (6 mL) was stirred overnight at room temperature andconcentrated under vacuum. This resulted in the title compound (60 mg)as a brown solid.

Step 6: Preparation of(2R,3S)-3-fluoro-N-([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2R,3S)-3-fluoro-N-([4-fluoro-3-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)pyrrolidine-2-carboxamidehydrochloride (60 mg, 0.14 mmol, 1.00 equiv), TEA (42 mg, 0.42 mmol,3.00 equiv), and 4-fluorobenzene-1-sulfonyl chloride (30 mg, 0.15 mmol,1.10 equiv) in dichloromethane (5 mL) was stirred for 3 h at roomtemperature. The diluted with 50 mL of DCM, washed with water, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:2). This resulted in the title compound (23.7mg, 31%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 9.02 (s, 1H), 8.01 (dd, J=7.2Hz, J=2.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.49-7.46 (m, 2H), 7.27-7.22 (m,3H), 5.44-5.31 (dd, J=50.4 Hz, J=2.4Hz, 1H), 4.63-4.49 (m, 2H),4.34-4.29 (d, J=22.0 Hz, 2H), 3.74 (t, J=9.2 Hz, 1H), 3.32-3.26 (m, 1H),2.16-1.90 (m, 2H).

Example 98 Preparation of(2R,3S)-3-fluoro-N-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl(2S,3R)-2-[([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(358 mg, 1.55 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL),[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanamine (420 mg,1.55 mmol, 1.00 equiv), DIEA (1 g, 7.74 mmol, 5.00 equiv), and HATU (707mg, 1.86 mmol, 1.20 equiv) was stirred for overnight at roomtemperature. The reaction was then diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1:1). This resulted in the title compound (400 mg, 53%) as a whitesolid.

Step 2: Preparation of tert-butyl(2R,3S)-3-fluoro-2-[([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (81 mg, 0.50 mmol, 1.20 equiv) was added dropwise into a solutionof tert-butyl(2S,3R)-2-[([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate (200 mg, 0.41 mmol, 1.00 equiv) in dichloromethane (20mL) at 0° C. under nitrogen. The resulting solution was stirred for 1 hat 5° C. in a water/ice bath. The reaction was then quenched bysaturated sodium bicarbonate solution, extracted with dichloromethane,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (1:10). This resulted inthe title compound (100 mg, 50%) as colorless oil.

Step 3: Preparation of(2R,3S)-3-fluoro-N-[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]pyrrolidine-2-carboxamidehydrochloride

A solution of tert-butyl(2R,3S)-3-fluoro-2-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]carbamoyl)pyrrolidine-1-carboxylate(100 mg, 0.21 mmol, 1.00 equiv) in saturated HCl (20 mL) in 1,4-dioxanewas stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound (75 mg, 87%) as awhite solid.

Step 4: Preparation of(2R,3S)-3-fluoro-N-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2R,3S)-3-fluoro-N-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)pyrrolidine-2-carboxamidehydrochloride (75 mg, 0.18 mmol, 1.00 equiv) in dichloromethane (20 mL),TEA (182 mg, 1.80 mmol, 10.10 equiv), and 4-fluorobenzene-1-sulfonylchloride (53 mg, 0.27 mmol, 1.50 equiv) was stirred for 2 h at roomtemperature. The resulting solution was diluted with dichloromethane,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with dichloromethane/methanol (10:1) to afford the titlecompound (32.2 mg, 33%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 9.26 (s, 1H), 9.08-9.05 (m,1H), 8.03 (s, 1H), 8.00-7.95 (m, 3H), 7.51-7.47 (m, 2H), 7.39-7.37 (m,1H), 5.24-5.11 (d, J=52.4 Hz, 1H), 4.49-4.46 (m, 2H), 4.39- 4.33 (m,1H), 3.70-3.66 (m, 1H), 3.21-3.14 (m, 1H), 2.16-2.10 (m, 2H).

Example 99 and Example 100 Preparation of(2S,3aR,6aS)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide.

and(2S,3aS,6aR)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide.

Step 1: Preparation of 3,6-dioxabicyclo[3.1.0]hexane

m-CPBA (88 g, 509.95 mmol, 1.20 equiv) was added in several batches intoa solution of 2,5-dihydrofuran (30 g, 428.02 mmol, 1.00 equiv) indichloromethane (300 mL) at 0° C. After 12 h at room temperature theresulting solution was diluted with saturated Na₂SO₃ and stirred for 0.5h at room temperature. The resulting mixture was washed with saturatedsodium bicarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum at low temperature. This resulted in the titlecompound (30 g, crude) as colorless oil

Step 2: Preparation of (3R,4S)-4-(prop-2-en-1-yl)oxolan-3-ol

Bromo(prop-2-en-1-yl)magnesium (300 mL, 2.06 mol, 2.00 equiv) was addeddropwise into a mixture of 3,6-dioxabicyclo[3.1.0]hexane (12.9 g, 149.84mmol, 1.00 equiv) and CuI (2.85 g, 14.96 mmol, 0.10 equiv) intetrahydrofuran (100 mL) at 0-5° C. under nitrogen. The resultingsolution was stirred for 3 h at 0° C., quenched by NH₄Cl (aq.), andextracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:6) to afford the title compound (5 g,26%) as light yellow oil.

Step 3: Preparation of 4-(prop-2-en-1-yl)oxolan-3-one

A mixture of (3S,4R)-4-(prop-2-en-1-yl)oxolan-3-ol (3.5 g, 27.31 mmol,1.00 equiv) and PCC (13 g, 60.31 mmol, 2.00 equiv) in dichloromethane(160 mL) was stirred for 12 h at room temperature. The reaction was thenquenched by water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (2.0 g, 58%) as a gray liquid.

Step 4: Preparation ofN-[(3Z)-4-(prop-2-en-1-yl)oxolan-3-ylidene]hydroxylamine

A mixture of 4-(prop-2-en-1-yl)oxolan-3-one (2.25 g, 17.84 mmol, 1.00equiv), NH₂OH.HCl (2.46 g, 35.40 mmol, 2.00 equiv), and pyridine (1.4 g,17.48 mmol, 1.00 equiv) in ethanol (50 mL) was stirred for 1.5 h at roomtemperature. The resulting mixture was concentrated under vacuum. Themixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:10) toafford the title compound (1.3 g, 52%) as colorless oil.

Step 5: Preparation of 4-(prop-2-en-1-yl)oxolan-3-amine

LiAlH₄ (1.186 g, 31.25 mmol, 3.00 equiv) was added batch wise into asolution of N-[(3Z)-4-(prop-2-en-1-yl)oxolan-3-ylidene]hydroxylamine(1.17 g, 8.29 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) at 0-5° C.under nitrogen. The resulting solution was stirred for 1 h at roomtemperature and 2 h at 45° C. The reaction was then quenched by aqueousNa₂SO₄. The solids were filtered out and the filtrate was concentratedunder vacuum. This resulted in the title compound (1.46 g, crude) as acolorless liquid.

Step 6: Preparation of4-fluoro-N-[4-(prop-2-en-1-yl)oxolan-3-yl]benzene-1-sulfonamide

A solution of 4-(prop-2-en-1-yl)oxolan-3-amine (1.35 g, 10.61 mmol, 1.00equiv), 4-fluorobenzene-1-sulfonyl chloride (1.65 g, 8.48 mmol, 0.80equiv), TEA (2.14 g, 21.15 mmol, 2.00 equiv), and4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.05 equiv) intetrahydrofuran (50 mL) was stirred for 1 h at room temperature. Themixture was diluted with water, extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:9) to afford the title compound (1.46g, 48%) as orange oil.

Step 7: Preparation of[1-[(4-fluorobenzene)sulfonyl]-hexahydro-1H-furo[3,4-b]pyrrol-2-yl]methanol

A mixture of4-fluoro-N-[4-(prop-2-en-1-yl)oxolan-3-yl]benzene-1-sulfonamide (1.57 g,5.50 mmol, 1.00 equiv), potassium peroxymonosulfate (6.77 g, 11.01 mmol,2.00 equiv), and TsOH (105.8 mg, 0.61 mmol, 0.10 equiv) in water (15mL)/MeCN (30 mL) was stirred for 12 h at 50° C. The reaction mixture wascooled to room temperature, quenched by saturated sodium bicarbonate,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:3)to afford the title compound (700 mg, 42%) as light yellow oil

Step 8: Preparation of1-[(4-fluorobenzene)sulfonyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxylicacid as an off-white

A solution of[1-[(4-fluorobenzene)sulfonyl]-hexahydro-1H-furo[3,4-b]pyrrol-2-yl]methanol(700 mg, 2.32 mmol, 1.00 equiv) in acetone (40 mL) was mixed with asolution of CrO₃ (1.163 g, 11.63 mmol, 5.00 equiv) in water(5 mL)containing sulfuric acid (1 mL). The resulting solution was stirred for2 h at room temperature. The reaction was then quenched by methanol.After 15 min the mixture was poured into 200 mL of brine. The resultingsolution was extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in the title compound (630 mg, 86%) as anoff-white solid.

Step 9: Preparation of(2S,3aR,6aS)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamideAnd(2R,3aS,6aR)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

A mixture of1-[(4-fluorobenzene)sulfonyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxylicacid (600 mg, 1.90 mmol, 1.00 equiv), HATU (794.2 mg, 2.09 mmol, 1.10equiv), DIEA (735.3 mg, 5.69 mmol, 3.00 equiv), and[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine hydrochloride(550 mg, 1.90 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL) wasstirred for 2 h at room temperature. The mixture was diluted with waterand extracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:3). The mixture was separated byChiral-Prep-HPLC to afford(2S,3aR,6aS)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide(47.9 mg, 5%) as a white solid. t_(R)=4.84 min (Repaired IA (CHIRALPAKIA), 0.46×10 cm, 5 μm, Hex(0.1% TEA):EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.26 (s, 1H), 8.28-8.26 (d, J=6 Hz, 2H),7.89-7.84 (m, 3H), 7.77-7.74 (d, J=9 Hz, 2H), 7.26-7.11 (m, 3H),4.68-4.60 (m, 2H), 4.55-4.50 (m, 2H), 4.10-4.06 (m, 1H), 3.73-3.70 (m,1H), 3.61-3.54 (m, 2H), 3.29-3.19 (m, 1H), 2.42-2.29 (m, 1H), 2.12-2.02(m, 1H).

(2R,3aS,6aR)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide(51.5 mg, 5%) was also isolated as a white solid. t_(R)=12.96 min (LuxCellulose-4, 0.46×15 cm, 5 μm, Hex(0.1% TEA):EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 8.36-8.34 (d, J=9 Hz, 2H), 8.05(s, 1H), 7.96-7.91 (m, 2H), 7.87-7.83 (b, 1H), 7.76-7.73 (d, J=9 Hz,2H), 7.33-7.26 (m, 2H), 4.85-4.64 (m, 2H), 4.42-4.38 (d, J=12 Hz, 1H),4.33-4.27 (m, 2H), 3.74-3.67 (m, 2H), 2.88-2.79 (m, 1H), 2.36-2.31 (m,1H), 1.94-1.83 (m, 1H).

(2S,3aS,6aR)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide(36 mg, 3%) was isolated as a white solid. t_(R) =3.27 min (Repaired IA(CHIRALPAK IA), 0.46×10 cm, 5 μm, Hex(0.1% TEA):EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.25 (s, 1H), 8.28-8.26 (d, J=6 Hz, 2H),7.89-7.84 (m, 3H), 7.77-7.74 (d, J=9 Hz, 2H), 7.26-7.12 (m, 3H),4.62-4.61 (m, 2H), 4.56-4.50 (m, 2H), 4.10-4.06 (m, 1H), 3.73-3.70 (m,1H), 3.58-3.53 (m, 2H), 3.29-3.19 (m, 1H), 2.35-2.28 (m, 1H), 2.12-2.02(m, 1H).

(2R,3aR,6aS)-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide(34.3 mg, 3%) was isolated as a white solid. t_(R)=6.60 min (LuxCellulose-4, 0.46×15 cm, 5 μm, Hex(0.1% TEA):EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 8.37-8.34 (d, J=8.5 Hz, 2H),8.04 (s, 1H), 7.96-7.91 (q, 2H), 7.86-7.83 (m, 1H), 7.76-7.73 (d, J=9Hz, 2H), 7.33-7.27 (m, 2H), 4.86-4.64 (m, 2H), 4.42-4.38 (d, J=12 Hz,1H), 4.33-4.27 (m, 2H), 3.74-3.67 (m, 2H), 2.86-2.82 (m, 1H), 2.36-2.31(m, 1H), 1.94-1.84 (m, 1H).

The stereochemistry for the bicyclic ring of the above compounds wasarbitrarily assigned. The 2-proline stereochemistry is as shown.

Example 101 Preparation of(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step1: Preparation of2,5-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine

A mixture of 2,5-dichloro-4-iodopyridine (10 g, 36.511 mmol, 1.00equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (6.7 g, 35.094mmol, 1.00 equiv), Pd(dppf)Cl₂(2.67 g, 3.649 mmol, 0.10 equiv),1,4-dioxane (250 mL), potassium carbonate (15 g, 108.534 mmol, 3.00equiv), and water (25 mL) was stirred for 12 h at 80° C. under nitrogen.The solids were filtered out and the solution was concentrated undervacuum. The residue was dissolved in ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1:20). This resulted in the titlecompound (9.9 g, 93%) as a white solid.

Step 2: Preparation of methyl5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carboxylate

A mixture of 2,5-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine(8.8 g, 30.027 mmol, 1.00 equiv), Pd(dppf)Cl₂ (2.2 g, 3.007 mmol, 0.10equiv), methanol (120 mL), TEA (9.1 g, 89.930 mmol, 2.995 equiv) wasstirred for 12 h at 60° C. under nitrogen. The solids were filtered out.The resulting solution was extracted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1:10). This resulted in thetitle compound (4.5 g, 47%) as a white solid.

Step 3: Preparation of[5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanol

DIBAL-H (47.5 mL, 1M in hexanes, 3.00 equiv) was added dropwise into asolution of methyl5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carboxylate (5.0g, 15.790 mmol, 1.00 equiv) in dichloromethane (200 mL) at −70° C. undernitrogen. The resulting solution was stirred for 30 min at −70° C. Thereaction was then quenched by methanol at −70° C. and then NaBH₄ (0.9 g)was added at 0° C. After 10 min at 0° C. the mixture was then quenchedby 1N of HCl at 0° C. The resulting solution was extracted with ethylacetate, washed with saturated sodium bicarbonate and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1:1). This resulted in the title compound (4.2g, 92%) as a light yellow solid.

Step 4: Preparation of2-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (6.0 g, 29.672 mmol, 1.992 equiv) was added dropwise into a mixtureof [5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanol(4.3 g, 14.897 mmol, 1.000 equiv), 2,3-dihydro-1H-isoindole-1,3-dione(4.4 g, 29.905 mmol, 2.008 equiv), and PPh₃ (7.8 g, 29.739 mmol, 1.996equiv) in tetrahydrofuran (200 mL) at 0° C. under nitrogen. After 12 hat room temperature the resulting mixture was concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (1:10). This resulted in the titlecompound (6.0 g, 96%) as an off-white solid.

Step 5: Preparation of[5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine

A mixture of2-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(6.0 g, 14.362 mmol, 1.000 equiv), methanol (150 mL), and NH₂NH₂.H₂O(7.2 g, 143.826 mmol, 10.014 equiv) was stirred for 12 h at roomtemperature. The resulting mixture was concentrated under vacuum and theresidue was dissolved in ethyl acetate. The solids were filtered out andthe liquid was concentrated under vacuum. This resulted in the titlecompound (7.5 g) as a light yellow solid.

Step 6: Preparation of tert-butyl(2S,4R)-2-[([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(4.1 g, 17.579 mmol, 1.00 equiv), N,N-dimethylformamide (50 mL), DIEA(4.5 g, 34.818 mmol, 1.98 equiv), HATU (7.9 g, 20.777 mmol, 1.18 equiv),and[5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(7.5 g, 26.072 mmol, 1.48 equiv) was stirred for 1 h at roomtemperature. The resulting solution was diluted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (1:1). This resulted inthe title compound (4.5 g, 51%) as an off-white solid.

Step 7: Preparation of(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamide

A solution of tert-butyl(2S,4R)-2-[([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(3.5 g, 6.960 mmol, 1.00 equiv) in dichloromethane (100 mL) andtrifluoroacetic acid (20 mL) was stirred for 2 h at room temperature.The resulting mixture was concentrated under vacuum. The residue wasdissolved in water. The pH value of the solution was adjusted to 8 withsaturated sodium bicarbonate. The resulting solution was extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (2.5g, 89%) as an off-white solid.

Step 8:(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-N-([5-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamide(2.5 g, 6.207 mmol, 1.00 equiv), dichloromethane (100 mL), TEA (1.9 g,18.777 mmol, 3.025 equiv), and 4-fluorobenzene-1-sulfonyl chloride (1.3g, 6.680 mmol, 1.08 equiv) was stirred for 12 h at room temperature. Theresulting solution was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/1). The crude product was purified byre-crystallization from ethyl acetate to afford the title compound (2.66g, 76%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.89 (m, 1H), 8.69 (s, 1H), 8.08-8.06 (m, 1H),7.89-7.80 (m, 3H), 7.67-7.64 (br, 1H), 7.47 (s, 1H), 7.28-7.21 (m, 2H),5.13-5.00 (d, J=52 Hz, 1H), 4.86-4.80 (m, 1H), 4.60-4.55 (m, 1H),4.30-4.26 (m, 1H), 3.94-3.61 (m, 2H), 2.55-2.21 (m, 2H).

Example 102 Preparation of(2S,4R)-4-fluoro-N-([5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-chloro-5-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 2-chloro-5-fluoro-4-iodopyridine (500 mg, 1.94 mmol, 1.00equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(544 mg, 2.14 mmol, 1.10 equiv), KOAc (572 mg, 5.83 mmol, 3.00 equiv),and Pd(dppf)Cl₂ (142 mg, 0.19 mmol, 0.10 equiv) in 1,4-dioxane (4 mL)was stirred for 14 h at 100° C. under nitrogen. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:5) to afford the title compound(272 mg) as a yellow solid.

Step 2: Preparation of2-(2-chloro-5-fluoropyridin-4-yl)-5-(trifluoromethyl)pyrazine

A mixture of (2-chloro-5-fluoropyridin-4-yl)boronic acid (3 g, 17.11mmol, 3.10 equiv), 2-chloro-5-(trifluoromethyl)pyrazine (1 g, 5.48 mmol,1.00 equiv), Pd(dppf)Cl₂ (200 mg, 0.27 mmol, 0.05 equiv), and potassiumcarbonate (2.26 g, 16.35 mmol, 3.00 equiv) in water (2 mL)/1,4-dioxane(20 mL) was stirred for 14 h at 75° C. under nitrogen. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10). This resultedin the title compound (500 mg, 33%) as a white solid.

Step 3: Preparation of5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridine-2-carbonitrile

A mixture of2-(2-chloro-5-fluoropyridin-4-yl)-5-(trifluoromethyl)pyrazine (500 mg,1.80 mmol, 1.00 equiv), Zn(CN)₂ (253 mg, 2.15 mmol, 1.20 equiv),Pd₂(dba)₃.CHCl₃ (186 mg, 0.18 mmol, 0.10 equiv), and dppf (200 mg, 0.36mmol, 0.20 equiv) in 10 mL of N,N-dimethylformamide was irradiated withmicrowave radiation for 1 h under nitrogen at 100° C. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10) to afford thetitle compound (250 mg, 52%) as a yellow solid

Step 4: Preparation of[5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl]methanaminehydrochloride

A suspension of5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridine-2-carbonitrile (200mg, 0.75 mmol, 1.00 equiv), palladium on carbon (50 mg), and hydrogenchloride (0.5 mL, conc.) in 20 mL of methanol was stirred for lmin atroom temperature under hydrogen. The solids were filtered out. Thefiltrate was concentrated under vacuum to afford the title compound (120mg) as a brown solid.

Step 5: Preparation of(2S,4R)-4-fluoro-N-([5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (47 mg, 0.16 mmol, 1.00 equiv),[5-fluoro-4-[5-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl]methanaminehydrochloride (50 mg, 0.16 mmol, 1.00 equiv), HATU (74 mg, 0.19 mmol,1.20 equiv), and DIEA (63 mg, 0.49 mmol, 3.00 equiv) in 3 mL oftetrahydrofuran was stirred for 14 h at room temperature. The mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The crude product was purified byPrep-HPLC to afford the title compound (19.7 mg, 22%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 9.11 (s, 1H), 8.67 (s, 1H), 8.21(s, 1H), 8.20-7.90 (m, 3H), 7.29-7.20 (m, 2H), 5.13-5.0 (d, J=39 Hz,1H), 4.80-4.76 (m, 1H), 4.28-4.24 (t, 1H), 3.92-3.75 (m, 2H), 2.55-2.45(m, 1H), 2.39-2.22 (m, 1H).

Example 103 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenylsulfonyl)-N-((3-methoxy-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl(2S,3S)-3-hydroxy-2-[([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,3S)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(108 mg, 0.47 mmol, 1.20 equiv), HATU (222 mg, 0.58 mmol, 1.50 equiv),DIEA (151 mg, 1.17 mmol, 3.00 equiv), and[3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanaminehydrochloride (120 mg, 0.39 mmol, 1.00 equiv) in N,N-dimethylformamide(10 mL) was stirred for 3 h at room temperature. The reaction mixturewas diluted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:4)to afford the title compound (150 mg, 79%) as a light yellow solid.

Step 2: Preparation of(2R,3S)-3-fluoro-2-[([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (109 mg, 0.48 mmol, 3.00 equiv) was added dropwise into a solutionof tert-butyl(2S,3R)-3-hydroxy-2-[([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(110 mg, 0.23 mmol, 1.0 equiv) in dichloromethane (10 mL) at 0° C. undernitrogen. The resulting solution was stirred for 15 min at 0° C. Thereaction was quenched by saturated sodium bicarbonate, extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1) to afford the title compound(65 mg, 59%) as a light yellow solid.

Step 3: Preparation of(2R,3S)-3-fluoro-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2R,3S)-3-fluoro-2-[([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(65 mg, 0.13 mmol, 1.00 equiv), and saturated HCl in 1,4-dioxane (5 mL).The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum to afford the titlecompound (61 mg) as yellow oil.

Step 4: Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenylsulfonyl)-N-((3-methoxy-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methyl)pyrrolidine-2-carboxamide

A solution of(2R,3S)-3-fluoro-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide hydrochloride (50 mg, 0.12 mmol,1.00 equiv), 4-fluorobenzene-1-sulfonyl chloride (25 mg, 0.13 mmol, 1.10equiv), 4-dimethylaminopyridine (1 mg, 0.01 mmol, 0.10 equiv), and TEA(30 mg, 0.30 mmol, 1.00 equiv) in dichloromethane (3 mL) was stirred for2 h at room temperature. The reaction mixture was diluted withdichloromethane, washed with water, dried with Na₂SO₄, and concentratedunder vacuum. The residue was purified by HPLC-Prep to afford the titlecompound (29.53 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.07-8.05 (m, 1H), 7.96 (s, 1H),7.89-7.86 (m, 2H), 7.73-7.70 (m, 1H), 7.52-7.36 (m, 1H), 7.28-7.23 (m,2H), 5.38-5.26 (d, J=50.4 Hz, 1H), 4.49-4.44 (m, 1H), 4.32-4.21 (m, 2H),4.05 (s, 3H), 3.77-3.72 (m, 1H), 3.31-3.24 (m, 1H), 2.15-1.85 (m, 2H).

Example 104 Preparation of(2S,4R)-4-fluoro-N-([6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid

n-BuLi (2.3 mL, 2.5M in hexanes, 1.50 equiv) was added dropwise into asolution of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (1 g, 3.86mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at −78° C. under nitrogen.After 1 h at −78° C. tris(propan-2-yl) borate (1.1 g, 5.85 mmol, 1.50equiv) was added dropwise at −78° C. The resulting solution was stirredfor 14 h at room temperature and quenched by 3N NaOH. The resultingsolution was stirred for 30 min at room temperature. The pH value of thesolution was adjusted to 7 with 3N aqueous hydrogen chloride. Theresulting mixture was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (1.6g) as yellow oil.

Step 2: Preparationof4-chloro-6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidine

A mixture of [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (500 mg,2.23 mmol, 1.00 equiv), 4,6-dichloropyrimidine (660 mg, 4.43 mmol, 2.00equiv), Pd(dppf)Cl₂ (82 mg, 0.11 mmol, 0.05 equiv), and potassiumcarbonate (616 mg, 4.46 mmol, 2.00 equiv) in water(1 mL)/1,4-dioxane (10mL) was stirred for 14 h at 75° C. under nitrogen. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10) to afford thetitle compound (150 mg, 23%) as a white solid.

Step 3: Preparationof6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile

A mixture of 4-chloro-6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidine(150 mg, 0.51 mmol, 1.00 equiv), Zn(CN)₂ (72 mg, 0.61 mmol, 1.20 equiv),Pd₂(dba)₃.CHCl₃ (53 mg, 0.05 mmol, 0.10 equiv), and dppf (57 mg, 0.10mmol, 0.20 equiv) in N,N-dimethylformamide (5 mL) was irradiated withmicrowave radiation for 1 h at 100° C. under nitrogen. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10). This resultedin the title compound (120 mg, 83%) as a yellow solid.

Step 4: Preparationof[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanaminehydrochloride

A mixture of6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile (120mg, 0.42 mmol, 1.00 equiv), palladium on carbon (40 mg, 0.38 mmol, 0.90equiv), and hydrogen chloride(6M, 0.1 mL) in methanol (20 mL) wasstirred for 20 min at room temperature under hydrogen. The solids werefiltered out. The filtrate was concentrated under vacuum to afford thetitle compound (133 mg, 97%) as a brown solid.

Step 4: Preparation of(2S,4R)-4-fluoro-N-([6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (119 mg, 0.41 mmol, 1.00 equiv),[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanaminehydrochloride (133 mg, 0.41 mmol, 1.00 equiv), EDCI (158 mg, 0.82 mmol,2.00 equiv), HOBT (61 mg, 0.45 mmol, 1.10 equiv), and DIEA (159 mg, 1.23mmol, 3.00 equiv) in tetrahydrofuran (10 mL) was stirred for 14 h atroom temperature. The mixture was diluted with water and extracted withethyl acetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC to afford the title compound (6.6 mg,3%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.16-8.12 (m, 1H), 8.06-8.02 (m,2H), 7.96-7.91 (m, 2H), 7.65 (s, 1H), 7.44-7.38 (t, J=8.7 Hz, 1H),7.28-7.23 (m, 1H), 5.17-4.90 (m, 2H), 4.61-4.54 (dd, J=3.9 Hz, J=3.6 Hz,1H), 4.35-4.29 (t, J=8.7 Hz, 1H), 3.96-3.66 (m, 2H), 2.61-2.53 (m, 1H),2.35-2.18 (m,1H).

Example 105 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-[[2-(methylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butylN-[4-oxo-4-[4-(trifluoromethyl)phenyl]but-2-yn-1-yl]carbamate

A mixture of tert-butyl N-(prop-2-yn-1-yl)carbamate (5 g, 32.22 mmol,1.0 equiv), Pd(PPh₃)₂Cl₂ (2.25 g, 3.21 mmol, 0.10 equiv), CuI (1.84 g,9.66 mmol, 0.20 equiv), 4-(trifluoromethyl)benzoyl chloride (6.5 g,31.17 mmol, 1.00 equiv), and TEA (3.2 g, 31.62 mmol, 1.0 equiv) in THF(150 mL) was stirred for 20 min at room temperature. The solids werefiltered out the liquid was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:5). This resulted in the title compound (10 g, 98%) as a brownsolid.

Step 2: Preparation of tert-butylN-[[2-(benzylsulfanyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]carbamate

A mixture of tert-butylN-[4-oxo-4-[4-(trifluoromethyl)phenyl]but-2-yn-1-yl]carbamate (10 g,30.55 mmol, 1.0 equiv), benzyl carbamimidothioate hydrochloride (6.3 g,31.08 mmol, 1.00 equiv), and potassium carbonate (6.35 g, 45.95 mmol,1.50 equiv) in CH₃CN (150 mL) was stirred for 2 h at room temperature.The reaction mixture was diluted with ethyl acetate, washed with water,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:5). This resulted in the title compound (7 g,48%) as a yellow solid.

Step 3: Preparation of[2-(benzylsulfanyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanaminehydrochloride

A solution of tert-butylN-[[2-(benzylsulfanyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]carbamate(3 g, 6.31 mmol, 1.00 equiv) and saturated HCl in 1,4-dioxane (50 mL)was stirred for overnight at room temperature. The solids were collectedby filtration. This resulted in the title compound (2.5 g, 96%) as alight brown solid.

Step 4: Preparation of(2S,4R)-N-[[2-(benzylsulfanyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (276.5 mg, 0.95 mmol, 1.00 equiv), HATU (433 mg, 1.14 mmol, 1.20equiv), DIEA (367.5 mg,2.84 mmol, 3.0 equiv), and[2-(benzylsulfanyl)-6-[4(trifluoromethyl)phenyl]pyrimidin-4-yl]methanaminehydrochloride (400 mg, 0.97 mmol, 1.00 equiv) in N,N-dimethylformamide(10 mL) was stirred for 3 h at room temperature. The resulting mixturewas diluted with 50 mL of ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:1) to afford the title compound (360 mg, 57%) as light yellowoil.

Step 5: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-[[2-(phenylmethane)sulfonyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-N-[[2-(benzylsulfanyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(360 mg, 0.55 mmol, 1.00 equiv) and m-CPBA (385 mg, 2.23 mmol, 4.00equiv) in dichloromethane (30 mL) was stirred for 6 h at roomtemperature. The resulting mixture was diluted with 50 mL of DCM, washedwith aqueous sodium bicarbonate, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (2:3). This resultedin the title compound (260 mg, 69%) as colorless oil.

Step 6: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-[[2-(methylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-[[2-(phenylmethane)sulfonyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide(100 mg, 0.15 mmol, 1.00 equiv) and CH₃NH₂ (100 mg, 3.22 mmol, 21.00equiv) in CH₃CN (15 mL) was stirred for 5 h at room temperature. Thereaction mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC to afford the title compound (41.7 mg, 51%) of asa white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.25-8.19 (m, 2H), 7.93-7.89 (m, 3H),7.73-7.71 (m, 2H), 7.25-7.21 (m, 2H), 7.12 (s, 1H), 5.13-5.00 (d, J=52.0Hz, 1H), 4.67-4.61 (m, 1H), 4.45-4.39 (m, 1H), 4.36-4.32 (m, 1H),3.96-3.87 (m, 1H), 3.78-3.65 (m, 1H), 3.15 (s, 3H), 2.57-2.48 (m, 1H),2.41-2.28 (m, 1H).

Example 106 Preparation of(2S,3R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-3-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-benzyl 2-ethyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate

Cbz-Cl (70 g, 410.33 mmol, 2.00 equiv) in dichloromethane (50 mL) wasadded dropwise into a mixture of ethyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (40 g, 204.45mmol, 1.00 equiv) and TEA (83 g, 820.24 mmol, 4.00 equiv) indichloromethane (400 mL) at room temperature. The resulting solution wasstirred overnight at room temperature. The mixture was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (2:1) to afford the title compound(60 g) as light yellow oil.

Step 2: Preparation of 1-benzyl 2-ethyl(2S,4R)-4-[[(4-methylbenzene)sulfonyl]oxy]pyrrolidine-1,2-dicarboxylate

4-Methylbenzene-1-sulfonyl chloride (24.0 g, 125.89 mmol, 1.00 equiv) indichloromethane (200 mL) was added dropwise into a solution of 1-benzyl2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (18.6 g, 63.41mmol, 0.50 equiv), TEA (16.5 g, 163.06 mmol, 1.30 equiv), and4-dimethylaminopyridine (1.0 g, 8.19 mmol) in dichloromethane (1 L) atroom temperature. The resulting solution was stirred for 12 h at 30° C.The mixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1/5) toafford the title compound (25 g, 44%) as colorless oil.

Step 3: Preparation of 1-benzyl 2-ethyl(2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate

A mixture of (phenyldiselanyl)benzene (109 g, 349.21 mmol, 1.20 equiv)and NaBH₄ (13 g, 343.62 mmol, 1.20 equiv) in ethanol (600 mL) wasstirred for 30 min at room temperature. To this was added 1-benzyl2-ethyl(2S,4R)-4-[[(4-methylbenzene)sulfonyl]oxy]pyrrolidine-1,2-dicarboxylate(78 g, 174.30 mmol, 1.00 equiv). The resulting solution was refluxedovernight and concentrated under vacuum. The residue was diluted withethyl acetate, washed with water, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn with ethyl acetate/petroleum ether (1/1) to afford the titlecompound (32 g, 42%) as colorless oil.

Step 4: Preparation of 1-benzyl 2-ethyl(2S)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate

Pyridine (52 mg, 0.66 mmol, 1.40 equiv) and H₂O₂ (30%, 131 mg, 3.85mmol, 2.50 equiv) was added sequentially into a solution of 1-benzyl2-ethyl (2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (200 mg,0.46 mmol, 1.00 equiv) in DCM (20 mL) at 0° C. The resulting solutionwas stirred for 2 h at room temperature, diluted with DCM, washed withwater, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:5). This resulted in the title compound(100 mg, 79%) as colorless oil.

Step 5: Preparation of 3-benzyl 2-ethyl(2S)-6-oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

m-CPBA (36 g, 208.62 mmol, 6.00 equiv) was added in portions to astirred solution of 1-benzyl 2-ethyl(2S)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (9.5 g, 34.51 mmol, 1.00equiv) in chloroform (300 mL). The resulting solution was heated toreflux for overnight. The resulting mixture was washed with saturatedsodium bicarbonate, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:5) to afford thetitle compound (4 g, 40%) as light yellow oil.

Step 6: Preparation of 1-benzyl 2-ethyl4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate

CH₃Li (20 mL, 5.00 equiv) was added dropwise into a mixture of CuI (2.8g, 14.70 mmol, 2.40 equiv) in ether (60 mL) at −10° C. under nitrogen.After 20 min at −10° C. a solution of 3-benzyl 2-ethyl6-oxa-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.8 g, 6.18 mmol,1.00 equiv) in ether (13 mL) was added dropwise at −10° C. After 1 h at−10° C. the reaction was quenched by water, extracted with ethylacetate, dried over sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with petroleumether/diethyl ether (5:1) to afford the title compound (700 mg, 37%) aslight brown oil.

Step 7: Preparation of 1-benzyl 2-ethyl(2S)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate

DAST (8.4 g, 36.68 mmol, 6.00 equiv) was added dropwise into a solutionof 1-benzyl 2-ethyl (2S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate(2.7 g, 8.79 mmol, 1.00 equiv) in dichloromethane (100 mL) at 0° C.under nitrogen. The resulting solution was stirred overnight at roomtemperature, diluted with DCM, washed with saturated sodium bicarbonate,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with ethylacetate/petroleum ether (1:5) to afford the title compound (710 mg, 26%)as colorless oil.

Step 8: Preparation of(2S)-1-[(benzyloxy)carbonyl]-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

A mixture of 1-benzyl 2-ethyl(2S)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (710 mg, 2.30 mmol,1.00 equiv) and LiOH (276 mg, 11.52 mmol, 5.00 equiv) in methanol (30ml) was stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was diluted with water and the pHvalue of the solution was adjusted to 4 with diluted HCl. The resultingsolution was extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (480 mg, 74%) as crude oil.

Step 9: Preparation of (2S)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

A mixture of(2S)-1-[(benzyloxy)carbonyl]-4-fluoro-3-methylpyrrolidine-2-carboxylicacid (480 mg, 1.71 mmol, 1.00 equiv) and palladium on carbon (50 mg) inmethanol (30 mL) was stirred overnight at 35° C. under hydrogen. Thesolids were filtered out. The filtrate was concentrated under vacuum toafford the title compound (250 mg) as a light brown crude solid.

Step 10: Preparation of(2S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-3-methylpyrrolidine-2-carboxylicacid

A mixture of (2S)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid (250mg, 1.70 mmol, 1.00 equiv), TEA (515 mg, 5.09 mmol, 3.00 equiv), and4-fluorobenzene-1-sulfonyl chloride (330 mg, 1.70 mmol, 1.00 equiv) indichloromethane (20 mL) was stirred for 3 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith water. The pH value of the solution was adjusted to 10-11 withaqueous sodium carbonate. The resulting solution was washed with ethylacetate. The pH value of the aqueous layer was adjusted to ˜1 by dilutedHCl. The resulting solution was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (330 mg) as a brown solid which was used for thenext step without any further purification

Step 11: Preparation of(2R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-3-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-3-methylpyrrolidine-2-carboxylicacid (160 g, 524.08 mmol, 1.00 equiv), HATU (239 g, 628.57 mmol, 1.20equiv), DIEA (135 g, 1.04 mol, 2.00 equiv), and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (153 g, 526.37 mmol, 1.00 equiv) in N,N-dimethylformamide(5 mL) was stirred overnight at room temperature. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (4:1). The crudeproduct was separated by Chiral-Prep-HPLC to afford the title compound(7.3 mg) as a white solid. t_(R)=5.14 min (Lux Cellulose-4, 0.46×5 cm, 3μm, Hex:EtOH=80:20, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.51 (s, 1H), 9.26 (s, 1H), 8.70 (d, J=1.5 Hz,1H), 8.17 (s, 1H), 7.93-7.89 (m, 2H), 7.80-7.77 (d, J=8.1 Hz, 1H), 7.49(s, 1H), 7.29-7.23 (m, 2H), 5.04-4.96 (m, 1H), 4.89-4.71 (d, J=52.2 Hz,1H), 4.53-4.46 (m, 1H), 3.89-3.64 (m, 3H), 2.51-2.34 (m, 1H), 1.19 (d,J=6.6 Hz, 3H).

And(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-3-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(82 mg) was also isolated as a white solid. t_(R)=4.08 min (LuxCellulose-4, 0.46×5 cm, 3 μm, Hex:EtOH=80:20, 1.0 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.51 (s, 1H), 9.26 (s, 1H), 8.70 (d, J=1.5 Hz,1H), 8.17 (s, 1H), 7.93-7.89 (m, 2H), 7.80-7.77 (d, J=8.1 Hz, 1H), 7.49(s, 1H), 7.29-7.23 (m, 2H), 5.04-4.96 (dd, J=17.7 Hz, J=7.2 Hz, 1H),4.89-4.71(d, J=52.2 Hz, 1H), 4.53-4.46 (dd, J=18.0 Hz, J=4.2 Hz, 1H),3.89-3.64 (m, 3H), 2.51-2.34 (m, 1H), 1.19 (d, J=6.6 Hz, 3H).

The 3-proline stereochemistry for the above two compounds wasarbitrarily assigned. The 2-proline and 4-proline stereochemistry forthe above two compounds is as shown.

Example 107: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid

A mixture of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (6.45 g, 26.30 mmol, 1.00equiv) and LiOH (3.16 g, 131.95 mmol, 5.00 equiv) in water (50mL)/methanol (50 mL) was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue wasdissolved in water. The resulting solution was extracted with ethylacetate. The pH value of the water layer was adjusted to 4 with 1Mhydrogen chloride. The resulting mixture was extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (3.5 g,58%) as colorless syrup which was used for the next step without anyfurther purification.

Step 2: Preparation of(2S,4R)-4-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid(3.5 g, 15.14 mmol, 1.00 equiv), HATU (8.6 g, 22.62 mmol, 1.50 equiv),DIEA (7.84 g, 60.66 mmol, 4.00 equiv), and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (4.4 g, 15.14 mmol, 1.00 equiv) in N,N-dimethylformamide(300 mL) was stirred for 1 h at room temperature. The reaction was thenquenched by water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with dichloromethane/methanol (50:1). This resulted inthe title compound (6.8 g, 96%) as a light brown solid.

Step 3: Preparation of tert-butyl(2S)-4-oxo-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of tert-butyl(2S,4R)-4-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(1.23 g, 2.63 mmol, 1.00 equiv), Dess-Martin (1.34 g, 3.16 mmol, 1.20equiv) in dichloromethane (25 mL) was stirred for 12 h at roomtemperature. The reaction was then quenched by water. The resultingsolution was extracted with dichloromethane, washed with saturatedsodium bicarbonate solution and then brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:10).This resulted in the title compound (960 mg, 78%) as a yellow solid.

Step 4: Preparation of tert-butyl(2S)-4-hydroxy-4-methyl-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

MeMgBr (1.4 mL, 2.00 equiv) was added into a mixture of tert-butyl(2S)-4-oxo-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(960 mg, 2.06 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at −5° C.under nitrogen. The resulting solution was stirred for 5 h at 0° C.,quenched by saturated solution of NH₄Cl, and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with dichloromethane/methanol(50:1) to afford the title compound (250 mg, 25%) as a yellow solid.

Step 5: Preparation of tert-butyl(2S)-4-fluoro-4-methyl-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (170.6 mg, 0.74 mmol, 3.00 equiv) was added dropwise into a mixtureof tert-butyl(2S)-4-hydroxy-4-methyl-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(170 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (3 mL) at −10° C.under nitrogen. The resulting solution was stirred for 1 h at −10° C.,quenched by water, and extracted with dichloromethane. The combinedextracts were washed with saturated sodium bicarbonate and brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (160 mg, 94%) as an orange solid.

Step 6: Preparation of(2S)-4-fluoro-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S)-4-fluoro-4-methyl-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(200 mg, 0.41 mmol, 1.00 equiv) and saturated hydrogen chloride indioxane (5 mL) was stirred for 3 h at room temperature. The resultingsolution was concentrated under vacuum to afford the title compound (186mg) as an orange solid.

Step 7: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S)-4-fluoro-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(186 mg, 0.49 mmol, 1.00 equiv), TEA (196 mg, 1.94 mmol, 4.00 equiv),4-fluorobenzene-1-sulfonyl chloride (113 mg, 0.58 mmol, 1.20 equiv), and4-dimethylaminopyridine (6 mg, 0.05 mmol, 0.10 equiv) in dichloromethane(5 mL) was stirred for 3 h at room temperature. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3). The crudeproduct was purified by Prep-HPLC to afford the title compound (51.7 mg,20%) as a white solid. t_(R)=1.94 min (CHIRALPAK IC-3, 0.46×5 cm, 3 μm,Hex:EtOH=70:30, 1.0 ml/min).

¹H NMR (300 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.31 (s, 1H), 9.15-9.11 (t,J=6.1 Hz, 1H), 8.81-8.78 (d, J=9.2 Hz, 1H), 8.24 (s, 1H), 8.07-8.01 (m,3H), 7.50-7.44 (t, 2H), 4.54-4.52 (d, J=6.1 Hz, 2H), 4.28-4.24 (m, 1H),3.74-2.48 (m, 2H), 2.46-2.39 (m, 1H), 2.19-2.02 (m, 1H), 1.43-1.36 (d,J=9.0 Hz, 3H).

The 4-proline stereochemistry for the above compound was arbitrarilyassigned. The 2-proline stereochemistry for the above compound is asshown.

Example 108 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 2-chloro-4-iodo-5-methoxyl)yridine

Sodium hydride (1.2 g, 60% in mineral oil, 2.30 equiv) was added inportions to a stirred solution of 6-chloro-4-iodopyridin-3-olhydrochloride (3.80 g, 13.02 mmol, 1.00 equiv) in N,N-dimethylformamide(30 mL) at 0° C. under nitrogen. After 30 min at 0° C. CH₃I (2.22 g,15.64 mmol, 1.20 equiv) was added to the solution. The resultingsolution was stirred for 12 h at room temperature, quenched by water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with petroleum ether/ethylacetate (10:1). This resulted in the title compound (2.9 g, 83%) as awhite solid.

Step 2: Preparation of2-chloro-5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine

A mixture of 2-chloro-4-iodo-5-methoxyl)yridine (1 g, 3.71 mmol, 1.00equiv) in dioxane (30 mL), [6-(trifluoromethyl)pyridin-3-yl]boronic acid(710 mg, 3.72 mmol, 1.00 equiv), Pd(dppf)Cl₂ (271 mg, 0.37 mmol, 0.10equiv), potassium carbonate (1.532 g, 11.08 mmol, 3.00 equiv), and water(3 mL) was stirred for 5 h at 50° C. under nitrogen. The solids werefiltered out and the liquid was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting withpetroleum ether/ethyl acetate (100:3). This resulted in the titlecompound (510 mg, 48%) as a white solid.

Step 3: Preparation of5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of2-chloro-5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine (400 mg,1.39 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), Zn(CN)₂ (162mg, 1.38 mmol, 1.00 equiv), DPPF (77 mg, 0.14 mmol, 0.10 equiv), andPd₂(dba)₃.CHCl₃ (72 mg, 0.07 mmol, 0.05 equiv) was irradiated withmicrowave for 1 h at 110° C. under nitrogen. The reaction was thenquenched by water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (15:100). This resulted in the titlecompound (440 mg) as an off-white solid.

Step 4: Preparation of[5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile(150 mg, 0.54 mmol, 1.00 equiv), methanol (30 mL), palladium on carbon(30 mg), hydrogen chloride (0.6 mL, concentrated) was stirred for 1 h atroom temperature under hydrogen. The solids were filtered out and theliquid was concentrated under vacuum. This resulted in the titlecompound (325 mg) as a yellow solid.

Step 5: Preparation of (2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (291 mg, 1.00 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL),[5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride (320 mg, 1.00 mmol, 1.00 equiv), DIEA (1.29 g, 9.98 mmol,10.00 equiv), and HATU (570 mg, 1.50 mmol, 1.50 equiv) was stirred forovernight at room temperature. The reaction was then quenched by water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/10). This resulted in the title compound(55.7 mg, 10%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.95-8.90 (m, 2H), 8.48 (s, 1H), 8.28-8.25(m, 1H), 7.99-7.93 (m, 3H), 7.52 (s, 1H), 7.46-7.41 (m, 2H), 5.27-5.01(d, J=52.8 Hz, 1H), 4.46-4.42 (m, 2H),4.23-4.17 (m, 1H), 3.93 (s, 3H),3.70 (s, 1H), 3.62-3.57 (m, 1H), 2.39-2.00 (m, 2H).

Example 109 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-methoxy-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of(2R,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-methoxy-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2-carboxamide

A mixture of[5-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(150mg, 0.530 mmol, 1.000 equiv), DMF (5 mL), DIEA (190 mg, 1.470 mmol,2.776 equiv), HATU (280 mg, 0.736 mmol, 1.391 equiv), and(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (157 mg, 0.514 mmol, 0.971 equiv) was stirred for 2 h at roomtemperature. The reaction was then quenched by water, extracted withethyl acetate, washed with brine, dried over sodium sulfate, andconcentrated under vacuum. The residue was purified a silica gel columneluting with petroleum ether/ethyl acetate (1:1). The crude product (200mg) was re-purified by Chiral-Prep-HPLC eluting with Hex and ethanol(hold 20.0% ethanol in 20 min) to afford the title compound (89.5 mg,30%) as a white solid. t_(R)=2.68 min (CHIRALPAK IC, 4.6×100 mm, 5 μm,MeOH (0.1%)=10% to 50% in 4.0 min, hold 2.0 min at 50%, 4 ml/min).

¹H NMR (300 MHz, CD₃OD) δ 8.96 (s, 1H), 8.40 (s, 1H), 8.33 (d, J=1.5 Hz,1H), 8.00-7.96 (m, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.37-7.31(m, 2H), 5.20 (d, J=52.8 Hz, 1H), 4.86-4.49 (m, 2H), 4.07-3.95 (m, 4H),3.73-3.57 (m, 1H), 2.67-2.60 (m, 1H), 2.27-2.08 (m, 2H), 1.58 (s, 3H).

(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-methoxy-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2-carboxamide(37.1 mg, 12%) was also isolated as a white solid. t_(R)=2.46 min(CHIRALPAK IC, 4.6×100 mm, 5 μm, MeOH (0.1%)=10% to 50% in 4.0 min, hold2.0min at 50%, 4 ml/min).

¹H NMR (300 MHz, CD₃OD) δ 8.97 (s, 1H), 8.40 (s, 1H), 8.32-8.28 (m, 1H),7.94-7.90 (m, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.30-7.24 (m,2H), 5.20 (d, J=52.8 Hz, 1H), 4.64-4.51 (m, 2H), 3.99 (s, 3H), 3.86-3.75(m, 1H), 2.60-2.27 (m, 1H), 1.75 (s, 3H).

Example 110 Preparation of(2S,4R)-4-cyano-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4S)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid

A mixture of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5 g, 20.39 mmol, 1.00equiv), methanol (100 mL), water (20 mL), and sodium hydroxide (2.85 g,71.26 mmol, 3.50 equiv) was stirred for 12 h at 20° C. The resultingsolution was concentrated and dissolved in water. The pH value of thesolution was adjusted to 3-4 with 5% of HCl, extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (2.4 g, 51%) as a whitesolid.

Step 2: Preparation of tert-butyl(2S,4S)-4-hydroxy-2-[([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of(2S,4S)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid(500 mg, 2.16 mmol, 1.00 equiv), dichloromethane (20 mL), EDCI (412.5mg, 2.15 mmol, 1.00 equiv), HOBT (292.5 mg, 2.16 mmol, 1.00 equiv), and3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-ylmethanamine (600mg, 2.21 mmol, 1.00 equiv) was stirred for 1 h at 20° C. The resultingsolution was diluted with water, extracted with dichloromethane, driedover sodium sulfate, and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (20/1). This resulted in the title compound(630 mg, 60%) as a white solid.

Step 3: Preparation of(2S,4S)-4-hydroxy-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A solution of tert-butyl(2S,4S)-4-hydroxy-2-[([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(1.6 g, 3.30 mmol, 1.00 equiv) in dichloromethane (20 mL)/trifluoroacetic acid (4 mL) was stirred for 12 h at 20° C. The resultingmixture was concentrated under vacuum. The residue was dissolved inwater. The pH value of the solution was adjusted to 8-9 with sodiumbicarbonate. The resulting solution was extracted with ethyl acetate,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (1.2 g, 95%) as a yellow solid.

Step 4: Preparation of(2S,4S)-1-[(4-fluorobenzene)sulfonyl]-4-hydroxy-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A solution of(2S,4S)-4-hydroxy-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide(1.2 g, 3.12 mmol, 1.00 equiv), dichloromethane (60 mL), TEA (630 mg,6.23 mmol, 2.00 equiv), and 4-fluorobenzene-1-sulfonyl chloride (606 mg,3.11 mmol, 1.00 equiv) was stirred for 12 h at 20° C. The resultingsolution was diluted with water, extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1:1). This resulted in the title compound(1.1 g, 65%) as a white solid.

Step 5: Preparation of (3S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-[([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidin-3-yl4-methylbenzene-1-sulfonate

A mixture of(2S,4S)-1-[(4-fluorobenzene)sulfonyl]-4-hydroxy-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide(1.1 g, 2.03 mmol, 1.00 equiv), TEA (615 mg, 6.08 mmol, 3.00 equiv),Tesco (578 mg, 3.03 mmol, 1.50 equiv), and 4-dimethylaminopyridine (25mg, 0.20 mmol, 0.10 equiv) in dichloromethane (20 mL) was stirred for 24h at 20° C. The resulting solution was diluted with water and extractedwith ethyl acetate. The combined extracts were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/10) to afford the title compound (1 g, 71%)as a white solid.

Step 6: Preparation of(2S,4R)-4-cyano-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(3S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-[([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)carbamoyl]pyrrolidin-3-yl4-methylbenzene-1-sulfonate (1.1 g, 1.58 mmol, 1.00 equiv), DMSO (6 mL),and NaCN (93 mg, 1.90 mmol, 1.20 equiv) was stirred for 48 h at 50° C.The resulting solution was diluted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/1). The crude product waspurified by Prep-HPLC to afford the title compound (43.1 mg, 5%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 7.90-7.85 (m, 3H), 7.71-7.64 (m, 4H),7.31-7.26 (s, 2H), 4.35-4.23 (m, 3H), 4.05 (s, 3H), 3.87-3.83 (m, 1H),3.40-3.35 (m, 1H), 3.18-3.14 (m, 1H), 2.69-2.65 (m, 1H), 1.93-1.87 (m,1H).

Example 111 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine

A mixture of [4-(trifluoromethoxy)phenyl]boronic acid (5 g, 24.28 mmol,1.00 equiv) in 1,4-dioxane (50 mL), water (10 mL),4,6-dichloropyrimidine (3.59 g, 24.10 mmol, 1.00 equiv), potassiumcarbonate (6.67 g, 48.26 mmol, 1.00 equiv), and Pd(dppf)Cl₂ (1.2 g, 1.64mmol, 1.00 equiv) was stirred for 3 h at 80° C. under nitrogen. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The cruderesidue was purified by recrystallized from ethyl acetate/petroleumether (1/10) to afford the title compound (3.6 g, 54%) as a white solid.

Step 2: Preparation of6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile

A mixture of 4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine (500 mg,1.82 mmol, 1.00 equiv), Zn(CN)₂ (256 mg, 2.18 mmol, 1.20 equiv), dppf(150 mg, 0.27 mmol, 0.30 equiv), and Pd₂(dba)₃ (100 mg, 0.11 mmol, 0.20equiv) in N,N-dimethylformamide (5 mL) was irradiated with microwave for3 h at 100° C. under nitrogen. The reaction mixture was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/petroleum ether (1/10). This resulted inthe title compound (200 mg, 41%) as yellow oil.

Step 3: Preparation of[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanamine hydrochloride

A mixture of 6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile(200 mg, 0.75 mmol, 1.00 equiv), palladium on carbon (100 mg, 0.94 mmol,1.00 equiv), ethanol (10 mL), and concentrated hydrogen chloride (0.2mL) was stirred for 10 min at room temperature under hydrogen. Thesolids were filtered out and the liquid was concentrated under vacuum.This resulted in the title compound (65 mg, 32%) as a yellow solid.

Step 4: Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide

A mixture of [6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanaminehydrochloride (65 mg, 0.24 mmol, 1.00 equiv),(2R,3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (70 mg, 0.24 mmol, 1.00 equiv), DIPEA (93 mg, 0.72 mmol, 3.00equiv), and HATU (182 mg, 0.48 mmol, 2.00 equiv) in tetrahydrofuran (10mL) was stirred for 16 h at room temperature. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The crude product was purified bychromatograph on a silica gel eluting with ethyl acetate/petroleum ether(1/1). This resulted in the title compound (23 mg, 18%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.21-9.17 (m, 2H), 8.35 (d, J=6.6 Hz, 1H),8.05-8.01 (m, 3H), 7.54-7.49 (m, 4H), 5.33-5.15 (d, J=52.2 Hz, 1H),4.57-4.40 (m, 3H), 3.71-3.66 (t, J=6.6 Hz, 1H), 3.33-3.15 (m, 1H),2.27-2.01 (m, 2H).

Example 112 Preparation of(2S,4R)-N-[[3-cyano-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of (3-bromo-5-iodophenyl)methanol

BH₃.THF (51 mL, 1 mol/L in THF) dropwise was added dropwise into asolution of 3-bromo-5-iodobenzoic acid (10 g, 30.59 mmol, 1.00 equiv) inTHF (50 mL) at 0° C. under nitrogen. The resulting solution was stirredfor 12 h at room temperature. The reaction was then quenched by water at0° C. The resulting solution was extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (8.5 g, 89%) as an off-whitesolid.

Step 2: Preparation of 1-bromo-3-(chloromethyl)-5-iodobenzene

A mixture of (3-bromo-5-iodophenyl)methanol (3.00 g, 9.59 mmol, 1.00equiv), dichloromethane (20 mL), and sulfuryl dichloride (2.20 g, 19.21mmol, 2.00 equiv) was stirred for 1 h at 0° C. The resulting solutionwas diluted with water and extracted with dichloromethane. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10). This resultedin the title compound (2 g, 63%) as a white solid.

Step 3: Preparation of 2-[(3-bromo-5-iodophenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione

A mixture of 1-bromo-3-(chloromethyl)-5-iodobenzene (2.00 g, 6.04 mmol,1.00 equiv) and 2-potassio-2,3-dihydro-1H-isoindole-1,3-dione (1.68 g,9.07 mmol, 1.50 equiv) in DMF (15 mL) was stirred for 12 h at roomtemperature. The reaction mixture was diluted with water. The solidswere collected by filtration to afford the title compound (2.5 g, 94%)as a white solid.

Step 4: Preparation of (3-bromo-5-iodophenyl)methanamine

A mixture of2-[(3-bromo-5-iodophenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(3.00 g, 6.79 mmol, 1.00 equiv), methanol (50 mL), and NH₂NH₂.H₂O (3.40g, 67.92 mmol, 10.00 equiv) was stirred for 12 h at 50° C. The solidswere filtered out and the liquid was concentrated under vacuum. Theresidue was purified by a silica gel column eluting withdichloromethane/methanol (20:1). This resulted in the title compound (2g, 94%) as yellow oil.

Step 5: Preparation of(2S,4R)-N-[3-bromo-5-iodophenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (780.00 mg, 2.68 mmol, 1.00 equiv), DMF (10.01 mL), HATU (1527.34mg, 4.02 mmol, 1.50 equiv), DIEA (1038.31 mg, 8.03 mmol, 3.00 equiv),and (3-bromo-5-iodophenyl)methanamine (1002.44 mg, 3.21 mmol, 1.20equiv) was stirred for 12 h at room temperature. The resulting solutionwas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). This resultedin the title compound (1.2 g, 77%) as a white solid.

Step 6: Preparation of(2S,4R)-N-([3-bromo-5-[6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of [6-(trifluoromethyl)pyridin-3-yl]boronic acid (130.50 mg,0.68 mmol, 1.00 equiv),(2S,4R)-N-[3-bromo-5-iodophenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(400.01 mg, 0.68 mmol, 1.00 equiv), Pd(dppf)Cl₂ (50.02 mg, 0.07 mmol,0.10 equiv), potassium carbonate (380 mg, 2.75 mmol, 4.00 equiv), and1,4-dioxane (15 mL)/water(3 mL) was stirred for 12 h at 50° C. undernitrogen. The resulting solution was diluted with water and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:1). This resulted in the title compound (260mg, 63%) as a light yellow solid.

Step 7: Preparation of(2S,4R)-N-[[3-cyano-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-([3-bromo-5-[6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-4-fluoro-1-[(4fluorobenzene)su-lfonyl]-pyrrolidine-2-carboxamide(220 mg, 0.36 mmol, 1.00 equiv), DMF (3 mL), dppf (55 mg, 0.10 mmol,0.30 equiv), Zn(CN)₂ (43 mg, 0.37 mmol, 1.00 equiv), and Pd₂(dba)₃ (33mg, 0.04 mmol, 0.10 equiv) was irradiated with microwave radiation for 2h at 100° C. under nitrogen. The resulting solution was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1). The crude product (200 mg) waspurified by Prep-HPLC to afford the title compound (92 mg, 46%) as awhite solid.

¹H NMR (300 MHz, CDCl₃) δ 8.97 (s, 1H), 8.14-8.11 (m, 1H), 7.90-7.71 (m,7H), 7.43 (s, 1H), 7.26-7.21 (m, 2H), 5.05 (d, J=52.5 Hz, 1H), 4.87-4.80(m, 1H), 4.48-4.42 (m, 1H), 4.30-4.24 (m, 1H), 3.96-3.84 (m, 1H),3.72-3.49 (m, 1H), 2.61-2.41 (m, 1H), 2.35-2.00 (m, 1H).

Example 113 Preparation of(2S,4R)-4-fluoro-N-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of4-chloro-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine

A mixture of [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (1 g, 4.81mmol, 1.00 equiv), 4,6-dichloropyrimidine (2 g, 13.42 mmol, 3.00 equiv),potassium carbonate (1.66 g, 12.01 mmol, 2.50 equiv), and Pd(dppf)Cl₂(180 mg, 0.25 mmol, 0.05 equiv) in 1,4-dioxane (15 mL)/water(1 mL) wasstirred overnight at 100° C. under nitrogen. The reaction mixture wascooled to room temperature, quenched with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1) to afford thetitle compound (0.7 g, 53%) as a brown solid.

Step 2: Preparation of6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carbonitrile

A mixture of 4-chloro-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine(2.2 g, 7.95 mmol, 1.00 equiv), Zn(CN)₂ (564 mg, 4.80 mmol, 0.60 equiv),Pd₂(dba)₃.CHCl₃ (414 mg, 0.40 mmol, 0.05 equiv), dppf (446 mg, 0.80mmol, 0.10 equiv), and Zn (50 mg, 0.76 mmol, 0.10 equiv) in DMA (15 mL)was irradiated with microwave radiation for 1 h at 125° C. undernitrogen. The resulting mixture was cooled to room temperature, quenchedby water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:1) to afford the title compound (730 mg, 34%) as a brown solid.

Step 3: Preparation of[6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine

A mixture of6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carbonitrile (300 mg,1.12 mmol, 1.00 equiv) in ethyl acetate (5 mL), methanol (5 mL, 123.49mmol, 110.00 equiv), and Pd(OH)₂/C (200 mg, 1.42 mmol, 1.30 equiv) wasstirred for 15 h at room temperature under hydrogen. The solids werefiltered out and the liquid was concentrated under vacuum to afford thetitle compound 280 mg) as a brown oil.

Step 4: Preparation of(2S,4R)-4-fluoro-N-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A solution of[6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine (280mg, 1.03 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (300 mg, 1.03 mmol, 1.00 equiv), EDCI (297 mg, 1.55 mmol, 1.50equiv), HOBT (153 mg, 1.13 mmol, 1.10 equiv), and DIEA (267 mg, 2.07mmol, 2.00 equiv) in tetrahydrofuran (10 mL) was stirred for 10 h atroom temperature. The reaction was then quenched by water, extractedwith ethyl acetate, washed with brine, and concentrated under vacuum.The crude product was purified by Prep-HPLC to afford the title compound(28.4 mg, 5%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.41 (s, 1H), 8.35-8.29 (t, J=7.7 Hz, 1H),7.94-7.88 (m, 3H), 7.79 (s, 1H), 7.62-7.59 (d, J=7.5 Hz, 1H), 7.49-7.46(d, J=11.4 Hz, 1H), 7.31-7.20 (m, 2H), 5.16-4.99 (d, J=52.2 Hz, 1H),4.77-4.66 (s, 2H), 4.33-4.27 (t, J=8.5 Hz, 1H), 3.97-3.49 (m, 2H),2.60-2.46 (m, 1H), 2.42-2.04 (m, 1H).

Example 114 Preparation of(2S,4R)-4-fluoro-N-([6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carbonitrile

A mixture of 4-chloro-6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine(200 mg, 0.72 mmol, 1.00 equiv), dppf (80 mg, 0.14 mmol, 0.20 equiv),Zn(CN)₂ (124 mg, 1.06 mmol, 1.50 equiv), and Pd₂(dba)₃.CHCl₃ (72 mg,0.07 mmol, 0.10 equiv) in N,N-dimethylformamide (4 mL) was irradiatedwith microwave radiation for 2 h at 100° C. under nitrogen. The reactionwas then quenched by water. The resulting solution was extracted withethyl acetate, washed with brine, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:10) to afford the title compound (160 mg,80%) as a yellow solid.

Step 2: Preparation of[6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine

Into a 100-mL round-bottom flask was placed6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carbonitrile (160 mg,0.60 mmol, 1.00 equiv), palladium on carbon (160 mg, 1.50 mmol, 2.50equiv), methanol (5 mL), and ethyl acetate (5 mL). The resultingsolution was maintained with an atmosphere of H₂ for 10 min at roomtemperature. Then the solids were filtered out and the liquid wasconcentrated under vacuum. This resulted in the title compound (120 mg,74%) as a yellow solid.

Step 3: Preparation of(2S,4R)-4-fluoro-N-([6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of[6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine (120mg, 0.44 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (128 mg, 0.44 mmol, 1.00 equiv), EDCI (170 mg, 0.89 mmol, 2.00equiv), HOBT (65.7 mg, 0.49 mmol, 1.10 equiv), and DIEA (114 mg, 0.88mmol, 2.00 equiv) in tetrahydrofuran (4 mL) was stirred for 13 h at roomtemperature. The reaction was then quenched by water/ice, extracted withethyl acetate, and concentrated under vacuum. The crude product waspurified by Prep-HPLC to afford the title compound (34.7 mg, 14%) as awhite solid.

¹H NMR (300 MHz, CDCl₃) δ 9.21 (s, 1H), 8.19-8.08 (m, 3H), 7.95-7.86 (m,2H), 7.74-7.64 (m, 2H), 7.28-7.23 (m, 2H), 5.17-4.91 (m, 2H), 4.54-4.53(d, J=4.2 Hz, 1H), 4.36-4.30 (t, J=8.5 Hz, 1H), 3.95-3.65 (m, 2H),2.66-2.56 (m, 1H), 2.34-2.13 (m, 1H).

Example 115 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-butyl 2-methyl(3S)-3-fluoropyrrolidine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl(3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (760 mg, 3.10 mmol, 1.00equiv) in dichloromethane (20 mL, 314.60 mmol, 1.00 equiv) was addedDAST (1.1 g, 4.80 mmol, 3.00 equiv) dropwise with stirring at −78° C.under nitrogen. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by water, extracted withdichloromethane, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1) to afford thetitle compound (420 mg, 55%) as brown oil.

Step 2: Preparation of methyl (3S)-3-fluoropyrrolidine-2-carboxylatehydrochloride

A mixture of 1-tert-butyl 2-methyl(3S)-3-fluoropyrrolidine-1,2-dicarboxylate (420 mg, 1.70 mmol, 1.00equiv) and HCl (saturated solution in 10 mL of 1,4-dioxane) was stirredfor 3 h at room temperature. The reaction was concentrated under vacuumto afford the title compound (320 mg, crude) as brown oil.

Step 3: Preparation of methyl (3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylate

A mixture of methyl (3S)-3-fluoropyrrolidine-2-carboxylate hydrochloride(320 mg, 2.17 mmol, 1.00 equiv) in dichloromethane (20 mL), TEA (661 mg,6.53 mmol, 3.00 equiv), and 4-fluorobenzene-1-sulfonyl chloride (844 mg,4.34 mmol, 2.00 equiv) was stirred for 16 hours at room temperature. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:1) to afford the title compound (520 mg, 78%) as a brown solid.

Step 4:(3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylic acid

A mixture of methyl(3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylate(200 mg, 0.66 mmol, 1.00 equiv) in 1,4-dioxane (2 mL) and sulfuric acid(50%) (10 mL, 187.61 mmol, 1.00 equiv) was stirred for 1 h at 100° C.The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (228 mg,crude) as yellow oil.

Step 5: Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of[5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(100 mg, 0.37 mmol, 1.00 equiv) in DMF (10 mL),(3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylic acid(92 mg, 0.32 mmol, 1.00 equiv), DIPEA (133 mg, 1.03 mmol, 3.00 equiv),and HATU (258 mg, 0.68 mmol, 2.00 equiv) was stirred for 16 h at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with petroleum ether/ethyl acetate(1/1). This resulted in the title compound (45.2 mg, 23%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.11-9.09 (m, 1H), 8.73 (d, J=1.8 Hz, 1H),8.40 (d, J=7.8 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.99-7.95 (m, 2H), 7.71(d, J=6 Hz, 1H), 7.51 (t, J=8.7 Hz, 2H), 5.27-5.10 (d, J=51.6 Hz, 1H),4.59-4.35 (m, 3H), 3.68-3.62 (m, 1H), 3.21-3.12 (m, 1H), 2.27-2.08(m,2H).

Example 116 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-methoxy-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-bromo-3-(bromomethyl)-5-methoxybenzene

A mixture of NBS (5.31 g, 29.83 mmol, 1.20 equiv), AIBN (2.04 g, 12.42mmol, 0.50 equiv), CCl₄ (100 mL), and 1-bromo-3-methoxy-5-methylbenzene(5.00 g, 24.87 mmol, 1.00 equiv) was stirred for 12 h at 80° C. undernitrogen. The reaction was then quenched by water, extracted withdichloromethane, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:100) to afford thetitle compound (6 g, 86%) as a light yellow solid.

Step 2: Preparation of2-[(3-bromo-5-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione

A mixture of 2-potassio-2,3-dihydro-1H-isoindole-1,3-dione (5.95 g,32.12 mmol, 1.00 equiv), DMF (30 ml), and1-bromo-3-(bromomethyl)-5-methoxybenzene (6 g, 21.43 mmol, 1.00 equiv)was stirred for 12 h at 50° C. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:20) to afford the title compound (5 g, 45%) as a white solid.

Step 3: Preparation of (3-bromo-5-methoxyphenyl)methanamine

A mixture of2-[(3-bromo-5-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(4.90 g, 14.15 mmol, 1.00 equiv), methanol (50 mL), and NH₂NH₂.H₂O (7.09g, 141.63 mmol, 10.00 equiv) was stirred for 3 h at 50° C. The resultingmixture was concentrated under vacuum. The residue was dissolved inethyl acetate. The solids were filtered out and the filtrate wasconcentrated under vacuum to afford the title compound (3 g, 98%) asyellow oil.

Step 4: Preparation of(2S,4R)-N-[(3-bromo-5-methoxyphenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (1.00 g, 3.43 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL),HATU (1.96 g, 5.15 mmol, 1.50 equiv), DIEA (1.33 g, 10.29 mmol, 3.00equiv), and (3-bromo-5-methoxyphenyl)methanamine (890 mg, 4.12 mmol,1.20 equiv) was stirred for 12 h at room temperature. The resultingsolution was diluted with water, extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:1) to afford the title compound (1 g,60%) as a yellow solid.

Step 5: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-methoxy-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-[3-bromo-5-methoxyphenyl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(500 mg, 1.02 mmol, 1.00 equiv),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (400 mg, 2.10 mmol, 2.10equiv), Pd(dppf)Cl₂ (80 mg, 0.11 mmol, 0.10 equiv), potassium carbonate(560 mg, 4.05 mmol, 4.00 equiv), and 1,4-dioxane (20 mL)/water (4 mL)was stirred for 12 h at 100° C. under nitrogen. The resulting solutionwas diluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (2:1). The crude product (230 mg) was purifiedby Prep-HPLC to afford the title compound (152 mg, 27%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃) δ 8.94 (s, 1H), 8.08 (d, J=8.1 Hz ,1H),7.89-7.85 (m, 2H), 7.73 (d, J=8.1 Hz, 1H), 7.29-7.18 (m, 4H), 7.02 (d,J=9.3 Hz, 2H), 5.04 (d, J=51.3 Hz, 1H), 4.76-4.71 (m, 1H), 4.46-4.40 (m,1H), 4.31-4.28 (m, 1H), 3.94-3.82 (m, 4H), 3.70-3.52 (m, 1H), 2.55-2.47(m, 1H), 2.34-2.19 (m,1H).

Example 117 Preparation of(2S,4R)-N-([3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 3,5-difluoro-4-iodopyridine-2-carbonitrile

LDA (841.14 mg, 7.85 mmol, 1.10 equiv) was added dropwise into asolution of 3,5-difluoropyridine-2-carbonitrile (1.00 g, 7.14 mmol, 1.00equiv) in tetrahydrofuran (15 mL). at −78° C. under nitrogen. Afterbeing stirred for 30 min at −78° C. a solution of I₂ (1.81 g, 7.13 mmol,1.00 equiv) in tetrahydrofuran (8 mL) was added dropwise. The resultingreaction was stirred at −78° C. for 40 minutes, quenched by water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:5)to afford the title compound (920 mg, 48%) as a yellow solid.

Step 2: Preparation of3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of 3,5-difluoro-4-iodopyridine-2-carbonitrile (650.00 mg, 2.44mmol, 1.00 equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid(1399.64 mg, 7.33 mmol, 3.00 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (99.78 mg, 0.12mmol), and sodium carbonate (518.01 mg, 4.89 mmol, 2.00 equiv) inwater(4.5 mL)/toluene (40 mL) was stirred overnight at 70° C. undernitrogen. The reaction was then quenched by water, extracted withdichloromethane, and washed with brine. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:4) to afford the title compound (220 mg, 32%) as a white solid

Step 3: Preparation of[3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine

Into a 25-mL round-bottom flask was placed3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile(20 mg, 0.07 mmol, 1.00 equiv), methanol (15 mL), palladium on carbon(20 mg, 0.19 mmol, 2.70 equiv), and concentrated hydrogen chloride (0.05mL). To the above mixture hydrogen gas was introduced. The resultingsolution was stirred for 15 min at 25° C. The solids were filtered outand the liquid was concentrated under vacuum. This resulted in the titlecompound (20 mg) as a light yellow solid.

Step 4: Preparation of(2S,4R)-N-([3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of[3,5-difluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(50 mg, 0.17 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (50.3 mg, 0.17 mmol, 1.00 equiv), EDCI (66.4 mg, 0.35 mmol, 2.00equiv), HOBT (25.7 mg, 0.19 mmol, 1.10 equiv), and DIEA (44.6 mg, 0.35mmol, 2.00 equiv) in tetrahydrofuran (5 mL) was stirred for 10 h at roomtemperature. The reaction mixture was then quenched with water. Theresulting solution was extracted with ethyl acetate and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:5) to afford the title compound(10 mg, 10%) as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.91 (s, 1H), 8.52 (s, 1H), 8.10-8.07 (d,J=8.1 Hz, 1H), 7.92-7.81 (m, 4H), 7.23-7.20 (d, J=8.4 Hz, 2H), 5.16-4.99(d, J=52.2 Hz, 1H), 4.75 (s, 2H), 4.33-4.27 (t, J=8.4 Hz, 1H), 3.99-3.86(m, 1H), 2.53-2.26 (m, 2H).

Example 118 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide.

Step1: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-methoxy-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-N-([6-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(55 mg, 0.10 mmol, 1.00 equiv), methanol (5 mL, 123.49 mmol, 1222.50equiv), and MeONa (6 mg, 0.11 mmol, 1.10 equiv) was stirred overnight at60° C. The reaction mixture was concentrated under vacuum, dissolved inwater, and extracted with ethyl acetate. The combined extracts weredried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product (48.6 mg) was purified by Prep-HPLC to afford the titlecompound (12.5 mg, 22%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.45-8.43 (m, 1H), 8.03-7.99 (m,2H), 7.90-7.88 (m, 1H), 7.56 (s, 1H), 7.37-7.32 (m, 2H), 7.09 (s, 1H),5.22-5.09 (d, J=52 Hz, 1H), 4.63-4.53 (m, 2H), 4.35-4.30 (m, 1H), 4.02(s, 3H), 3.90-3.70 (m, 2H), 2.54-2.16 (m, 2H).

Example 119 Preparation of(2S,4R)-4-fluoro-N-([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-chloro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbonitrile

A mixture of 2,6-dichloropyridine-4-carbonitrile (5.00 g, 28.90 mmol,1.00 equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (1.82 g, 9.53mmol, 0.30 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (1.18 g, 1.44 mmol, 0.05 equiv),sodium carbonate (6.13 g, 57.84 mmol, 2.00 equiv), and water (12mL)/1,4-dioxane (100 mL) was stirred for 1 h at 70° C. under nitrogen.The resulting mixture was concentrated under vacuum. The mixture wasdiluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/10) to afford the title compound (2.6g, 32%) as a white solid.

Step 2: Preparation of2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbonitrile

A mixture of2-chloro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbonitrile (1.5g, 5.29 mmol, 1.00 equiv), KF (928 mg, 15.97 mmol, 4.00 equiv), and 30mL of DMSO was stirred for 5 h at 110° C. under nitrogen. The reactionwas then quenched by water, extracted with ethyl acetate, washed withbrine, concentrated under vacuum, and dried over anhydrous sodiumsulfate. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/10) to afford the titlecompound (1.1 g, 78%) as a white solid.

Step 3: Preparation of[2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methanaminehydrochloride

A mixture of2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbonitrile (3g, 11.23 mmol, 1.00 equiv), palladium on carbon (500 mg), and hydrogenchloride (2 mL) in 60 mL of tetrahydrofuran was stirred for 12 h underhydrogen at 40° C. The solids were filtered out and the liquid wasconcentrated under vacuum. This resulted in the title compound (3 g,87%) as a light yellow solid.

Step 4: Preparation of tert-butyl(2S,4R)-4-fluoro-2-[([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(3 g, 12.86 mmol, 1.00 equiv), HOBT (1.74 g, 12.88 mmol, 1.10 equiv),EDCI (4.47 g, 23.32 mmol, 2.00 equiv), DIEA (3.02 g, 23.37 mmol, 2.00equiv), and[2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methanaminehydrochloride (3.6 g, 11.70 mmol, 1.00 equiv) in 300 mL oftetrahydrofuran was stirred for 2 h at room temperature. The resultingmixture was diluted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1:2). This resulted in the title compound (4 g,64%) as a light yellow solid.

Step 5: Preparation of(2S,4R)-4-fluoro-N-([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-4-fluoro-2-[([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(4 g, 8.22 mmol, 1.00 equiv) in 100 mL HCl (a saturated solution in1,4-dioxane) was stirred for 2 h at 40° C. The solids were collected byfiltration and washed with hexane to afford the title compound (4 g) asa light yellow solid.

Step 6: Preparation of(2S,4R)-4-fluoro-N-([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-N-([2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (4 g, 9.46 mmol, 1.00 equiv), 4-dimethylaminopyridine (115mg, 0.94 mmol, 0.10 equiv), TEA (3.83 g, 37.85 mmol, 4.00 equiv), and4-fluorobenzene-1-sulfonyl chloride (2.2 g, 11.30 mmol, 1.20 equiv) in200 mL of dichloromethane was stirred for 3 h at 40° C. The resultingsolution was diluted with dichloromethane, washed with brine, dried oversodium sulfate, and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1:1) to afford the title compound (1.204 g,23%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.58-8.56 (m, 1H), 7.92-7.88 (m,2H), 7.83 (s, 1H), 7.78-7.76 (d, J=8.4 Hz, 1H), 7.49 (s, 1H), 7.27-7.23(m, 2H), 6.97 (s, 1H), 5.13-4.99 (d, J=51.6 Hz, 1H), 4.89-4.83 (m, 1H),4.47-4.42 (m, 1H), 4.32-4.28 (m, 1H), 3.96-3.87 (m, 1H), 3.74-3.59 (m,1H), 2.60-2.58 (m, 1H), 2.31-2.12 (m, 1H).

Example 120 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of 2,6-dichloro-4-iodopyridine (7.00 g, 25.56 mmol, 1.00equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (4.88 g, 25.56mmol, 1.00 equiv), 1,4-dioxane (100 mL), sodium carbonate (5.42 g, 51.14mmol, 2.00 equiv), and water (2 mL) was stirred overnight at 100° C.under nitrogen. The reaction was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/20) to afford thetitle compound (6.5 g, 87%) as a light yellow solid.

Step 2: Preparation of6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of 2,6-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine(5.00 g, 17.06 mmol, 1.00 equiv), DMSO (15 mL, 211.18 mmol, 12.40equiv), and KF (990 mg, 17.04 mmol, 1.00 equiv) was stirred overnight at150° C. in an oil bath. The reaction was cooled to room temperature,diluted with water, extracted with of ethyl acetate, washed with brine,dried oven anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/20) to afford the title compound (3.8 g, 81%)as a white solid.

Step 3: Preparation of6-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of6-chloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile (1g, 3.53 mmol, 1.00 equiv), Zn(CN)₂ (420 mg, 3.58 mmol, 1.00 equiv), Zn(20 mg, 0.31 mmol, 0.09 equiv), Pd₂(dba)₃.CHCl₃ (190 mg, 0.18 mmol, 0.05equiv), dppf (100 mg, 0.18 mmol, 0.05 equiv), and DMA (4 mL, 43.02 mmol,12.20 equiv) was irradiated with microwave radiation for 1 h at 125° C.under nitrogen. The reaction was then quenched by water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/20) to afford thetitle compound (410 mg) as a white solid.

Step 4: Preparation of[6-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of6-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile (200mg, 0.75 mmol, 1.00 equiv), tetrahydrofuran (30 mL), palladium on carbon(200 mg, 1.88 mmol, 2.50 equiv), and concentrated hydrogen chloride (0.1mL) was stirred for 8 h at 25° C. The solids were filtered out. Thefiltrate was concentrated under vacuum to afford the title compound (200mg) as a light yellow solid which was used for the next step without anyfurther purification.

Step 5: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[6-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (214.79 mg, 0.74 mmol, 1.00 equiv),[6-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride (200.00 mg, 0.74 mmol, 1.00 equiv), tetrahydrofuran (10mL), HOBT (109.61 mg, 0.81 mmol, 1.10 equiv), EDCI (282.73 mg, 1.47mmol, 2.00 equiv), and DIEA (190.61 mg, 1.47 mmol, 2.00 equiv) wasstirred overnight at 25° C. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The crude product (50.8mg) was purified by Prep-HPLC to afford the title compound (21.2 mg, 5%)as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.18 (s, 1H), 8.52-8.49 (m, 2H), 8.04-8.00 (m,2H), 8.00-7.91 (m, 2H),7.43 (s, 1H),7.38-7.33 (m, 2H), 5.23-5.10 (d,J=52 Hz, 1H), 4.65-4.54 (m, 2H), 4.33-4.29 (m, 1H), 3.86-3.71 (m, 2H),2.54-2.53 (m, 1H), 2.30-2.16 (m, 1H).

Example 121 Preparation of(2S,4R)-4-fluoro-N-([5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl3-(trifluoromethyl)-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate(20 g, 88.78 mmol, 1.00 equiv), trimethyl(trifluoromethyl)silane (38 g,267.24 mmol, 3.00 equiv), and TBAF (4 mL, 61.02 mmol, 1.00 equiv) intetrahydrofuran (180 ml) was stirred for 1 day at 60° C. andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10) to afford thetitle compound (19 g, 58%) as yellow oil.

Step 2: Preparation of tert-butyl3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl3-(trifluoromethyl)-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate(7.0 g, 19.05 mmol, 1.0 equiv) and potassium methaneperoxoate (4 g,28.73 mmol, 1.50 equiv) in methanol (100 mL) was stirred for 30 min atroom temperature and concentrated under vacuum. The resulting solutionwas diluted with 50 mL of ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (6 g) as a light yellow solid.

Step 3: Preparation of 3-(trifluoromethyl)-8-azabicyclo[3.2.1]oct-2-ene

Thionyl chloride (7 g, 58.84 mmol, 6.00 equiv) and pyridine (4.7 g,59.42 mmol, 6.0 equiv) was added dropwise into a solution of tert-butyl3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (3g,10.16 mmol, 1.00 equiv), 4-dimethylaminopyridine (122 mg, 0.10 equiv)in 1,4-dioxane (100 mL) at 0° C. The resulting solution was heated to60° C. for 12 h, quenched with sodium bicarbonate solution (200 ml),extracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:10) to afford thetitle compound (900 mg, 50%) as a light yellow solid

Step 4: Preparation of tert-butyl3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with anatmosphere of H₂ was placed tert-butyl3-(trifluoromethyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (900 mg,3.25 mmol, 1.00 equiv), and palladium on carbon (30 mg) in methanol (15mL). The resulting solution was stirred overnight at room temperature.The solids were filtered out and the liquid was concentrated undervacuum. This resulted in the title compound (800 mg, 88%) as lightyellow oil

Step 5: Preparation of 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octanehydrochloride

A solution of tert-butyl3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg,2.86 mmol, 1.00 equiv) and saturated HCl in 1,4-dioxane (20 mL) wasstirred for 2 h at room temperature and concentrated under vacuum. Thisresulted in the title compound (400 mg, 65%) as a white solid

Step 6: Preparation of8-(2-chloro-5-fluoropyridin-4-yl)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane

Into a 20-mL sealed tube purged and maintained with an inert atmosphereof nitrogen was placed 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octanehydrochloride (400 mg, 1.85 mmol, 1.00 equiv),2-chloro-5-fluoro-4-iodopyridine (860 mg, 3.34 mmol, 1.80 equiv),Pd₂(dba)₃CHCl₃ (385 mg, 0.37 mmol, 0.20 equiv), Xantphos (400 mg, 0.69mmol, 0.40 equiv), Cs₂CO₃ (1.8 g, 5.52 mmol, 3.00 equiv), andmethylbenzene (6 mL). The resulting solution was stirred overnight at110° C. and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 580 mg of the title compound as a light brown solid

Step 7: Preparation of5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carbonitrile

Into a 20-mL sealed tube purged and maintained with an inert atmosphereof nitrogen was placed8-(2-chloro-5-fluoropyridin-4-yl)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane(760 mg, 2.46 mmol, 1.00 equiv), Pd₂(dba)₃CHCl₃ (248 mg, 0.24 mmol, 0.10equiv), dppf (265 mg, 0.48 mmol, 0.20 equiv), zinc dicarbonitrile (282mg, 2.40 mmol, 1.00 equiv), Zn (15.5 mg, 0.24 mmol, 0.10 equiv), and DMA(8 mL). The resulting solution was stirred overnight at 110° C., dilutedwith 20 mL of water, extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:3)to afford the title compound (120 mg, 16%) as a white solid.

Step 8: Preparation of[5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]methanaminehydrochloride

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of H₂ was placed5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carbonitrile(120 mg, 0.40 mmol, 1.00 equiv), methanol (20 mL), palladium on carbon(100 mg), and hydrogen chloride (0.5 mL). The resulting solution wasstirred for 20 min at room temperature. The solids were filtered out andthe liquid was concentrated under vacuum. This resulted in the titlecompound 120 mg (88%) as a light brown solid.

Step 9: Preparation of(2S,4R)-4-fluoro-N-([5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (170 mg, 0.58 mmol, 1.50 equiv), HATU (227 mg, 0.60 mmol, 1.50equiv), DIEA (154 mg, 1.19 mmol, 3.00 equiv), and[5-fluoro-4-[3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]methanaminehydrochloride (120 mg, 0.35 mmol, 1.00 equiv) in N,N-dimethylformamide(3 mL) was stirred for 2 h at room temperature. The resulting mixturewas diluted with ethyl acetate, washed with brine, dried over sodiumsulfate, and concentrated under vacuum. The crude product was purifiedby Prep-HPLC to afford the title compound 56.8 mg (28%) of as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.86-8.84 (m ,1H), 8.15-8.13 (d, J=6.0 Hz,1H), 8.01-7.96 (m, 2H), 7.49-7.43 (t, J=9.0 Hz, 2H), 6.92-6.89 (d, J=8.1Hz, 2H), 5.27-5.10 (d, J=51.3 Hz, 1H), 4.53 (s, 2H), 4.39-4.16 (m, 3H),3.71 (s, 1H), 3.61-3.59 (m, 1H), 2.95 (s, 1H), 2.42-2.35 (m, 1H),2.14-2.07 (s, 1H), 2.00-1.96 (m, 2H), 1.90-1.85 (m, 2H), 1.83-1.60 (m,4H).

Example 122 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of ethyl 3-bromo-5-fluorobenzoate

A mixture of 3-bromo-5-fluorobenzoic acid (2 g, 9.13 mmol, 1.00 equiv),ethanol (40 mL), and sulfuric acid (3 mL) was stirred overnight at 85°C. in an oil bath. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. This resulted in thetitle compound (1.9 g, 84%) as a light brown solid.

Step 2: Preparation of ethyl3-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of ethyl 3-bromo-5-fluorobenzoate (800 mg, 3.24 mmol, 1.00equiv) in dioxane (30 mL),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.24 g, 4.88 mmol, 1.50 equiv), AcOK (959 mg, 9.77 mmol, 3.00 equiv),and Pd(dppf)Cl₂ (477 mg, 0.65 mmol, 0.20 equiv) was stirred overnight at90° C. under nitrogen. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. This resulted in thetitle compound (700 mg, crude) as a black crude solid.

Step 3: Preparation of ethyl3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]benzoate

A mixture of ethyl3-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (700 mg, 2.38mmol, 1.00 equiv) in dioxane (15 mL),2-chloro-5-(trifluoromethyl)pyrazine (437 mg, 2.39 mmol, 1.00 equiv),Pd(dppf)Cl2 (352 mg, 0.48 mmol, 0.20 equiv), and Cs₂CO₃ (2.35 g, 7.21mmol, 3.00 equiv) was stirred overnight at 90° C. under nitrogen. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:100) to afford the title compound(300 mg, 40%) as an off-white solid.

Step 4: Preparation of[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanol

LiAlH₄ (73 mg, 1.92 mmol, 2.00 equiv) was added in several batches intoa solution of ethyl 3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]benzoate(300 mg, 0.95 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0° C.under nitrogen. After 10 min at 0° C. the reaction was quenched bywater. The solids were filtered out and the filtrate was concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (7:100) to afford the title compound(160 mg, 62%) as an off-white solid.

Step 5: Preparation of2-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (134 mg, 0.66 mmol, 1.20 equiv) was added dropwise into a solutionof [3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanol (150 mg,0.55 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindole-1,3-dione (98 mg, 0.67mmol, 1.20 equiv), and PPh₃ (288 mg, 1.10 mmol, 2.00 equiv) in 10 mL ofTHF at 0° C. under nitrogen. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (7:100) to afford the title compound(230 mg) as a white solid.

Step 6: Preparation of[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanamine

A solution of2-([3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(230 mg, 0.57 mmol, 1.00 equiv) in ethanol (7 mL) and NH₂NH₂H₂O (7 mL,144.03 mmol, 251.30 equiv) was stirred overnight at 60° C. The resultingmixture was concentrated under vacuum. The residue was purified by asilica gel column eluting with dichloromethane/methanol (100:10) toafford the title compound (100 mg, 64%) as an off-white solid.

Step 7: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methyl]pyrrolidine-2-carboxamide

A mixture of[3-fluoro-5-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]methanamine (104 mg,0.38 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (168 mg, 0.58 mmol, 1.50 equiv),N,N-dimethylformamide (5 mL), DIEA(150 mg, 1.16 mmol, 3.00 equiv), and HATU (220 mg, 0.58 mmol, 1.50equiv) was stirred overnight at room temperature. The reaction mixturewas diluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (20:100) to afford the title compound (15.7 mg,8%) as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 9.39-9.38 (m, 1H), 9.07 (s, 1H), 8.07 (s, 1H),8.00-7.88 (m, 3H), 7.37-7.30 (m, 3H), 5.50-5.22 (d, J=83.1 Hz, 1H), 4.58(s, 2H), 4.29-4.23 (m, 1H), 3.85-3.70 (m, 2H), 2.60-2.40 (m, 1H),2.39-2.04 (m, 1H).

Example 123 Preparation of(1R,3S,5R)-2-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide.

Step 1: Preparation of(5S)-5-[[(tert-butyldiphenylsilyl)oxy]methyl]pyrrolidin-2-one

A mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (20 g, 173.72 mmol,1.00 equiv), 1H-imidazole (26 g, 381.92 mmol, 2.20 equiv),4-dimethylaminopyridine (2.12 g, 17.35 mmol, 0.10 equiv), and TBDPS-Cl(50 g, 181.91 mmol, 1.00 equiv) in dichloromethane (800 mL) was stirredovernight at room temperature. The reaction mixture was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (62.7 g, crude) as a colorless crystal.

Step 2: Preparation of tert-butyl(2S)-2-[[(tert-butyldiphenylsilyl)oxy]methyl]-5-oxopyrrolidine-1-carboxylate

A mixture of(5S)-5-[[(tert-butyldiphenylsilyl)oxy]methyl]pyrrolidin-2-one (62.7 g,177.35 mmol, 1.00 equiv), 4-dimethylaminopyridine (24 g, 196.45 mmol,1.10 equiv), and di-tert-butyl dicarbonate (38.6 g, 176.86 mmol, 1.00equiv) in acetonitrile (800 mL) was stirred for 16 h at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with petroleum ether/ethyl acetate (50:1) to afford thetitle compound (45 g, 56%) as a white solid.

Step 3: Preparation of tert-butyl(2S)-2-[[(tert-butyldiphenylsilyl)oxy]methyl]-2,3-dihydro-1H-pyrrole-1-carboxylate

Lithium triethylborohydride (23 mL, 217.10 mmol, 9.80 equiv) was addeddropwise into a solution of tert-butyl(2S)-2-[[(tert-butyldiphenylsilyl)oxy]methyl]-5-oxopyrrolidine-1-carboxylate(10.05 g, 22.15 mmol, 1.00 equiv) in toluene (36 mL) at −50° C. undernitrogen. After 30 min DIEA (16.5 mL, 99.84 mmol, 4.50 equiv),4-dimethylaminopyridine (34 mg, 0.28 mmol), and Tf₂O (3.6 mL, 21.31mmol, 1.00 equiv) was added sequentially at −50° C. The resultingsolution was stirred overnight at 20° C. The reaction was then quenchedby water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (3:100) to afford the title compound (4.321 g, 45%) as yellow oil.

Step 4: Preparation of tert-butyl(3S)-3-[[(tert-butyldiphenylsilyl)oxy]methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate

Diethylzinc (8.3 mL, 67.19 mmol, 1.10 equiv) was added dropwise into asolution of tert-butyl(2S)-2-[[(tert-butyldiphenylsilyl)oxy]methyl]-2,3-dihydro-1H-pyrrole-1-carboxylate(3.3 g, 7.54 mmol, 1.00 equiv) in dichloromethane (30 mL) at 0° C. Tothis was added diiodomethane (3.04 g, 11.35 mmol, 1.50 equiv) dropwisewith stirring at 0° C. After 30 min at 0° C. the resulting solution wasstirred for 4 h at 20° C. The pH value of the solution was adjusted to 8with saturated sodium carbonate solution. The resulting solution wasextracted with dichloromethane, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:50)to afford the title compound (2 g, 59%) as colorless oil.

Step 5: Preparation of tert-butyl(3S)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A mixture of tert-butyl(3S)-3-[[(tert-butyldiphenylsilyl)oxy]methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.6 g, 3.54 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) and TBAF (3.5mL, 13.39 mmol, 1.00 equiv) was stirred for overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:10) to afford the title compound (900 mg) ascolorless oil.

Step 6: Preparation of(3S)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

A mixture of tert-butyl(3S)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (900 mg,4.22 mmol, 1.00 equiv) in CH₃CN (10 mL)/CCl₄ (10 mL), NaI0₄ (2.72 g,12.72 mmol, 3.00 equiv) in water (10 mL), and RuCl₃.H₂O (44 mg, 0.20mmol) was stirred for overnight at room temperature. The reactionmixture was diluted with water, extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (620 mg, 65%) as a brownsolid.

Step 7: Preparation of tert-butyl(3S)-3-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate

A mixture of(3S)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (620 mg, 2.73 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL),[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (955 mg, 3.29 mmol, 1.20 equiv), DIEA (3.52 g, 27.24 mmol,10.00 equiv), and HATU (1.246 g, 3.28 mmol, 1.20 equiv) was stirredovernight at room temperature. The reaction mixture was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (30:100) to afford the title compound (700 mg, 55%) as a yellowsolid.

Step 8: Preparation of(3S)-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride

A mixture of tert-butyl(3S)-3-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate(700 mg, 1.51 mmol, 1.00 equiv) and HCl (saturated solution in 50 mL of1,4-dioxane) was stirred for 20 min at room temperature. The resultingmixture was concentrated under vacuum to afford the title compound (790mg, crude) as a yellow solid.

Step 9: Preparation of(1R,3S,5R)-2-(4-fluorophenyl)sulfonyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide

A mixture of(3S)-2-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(700 mg, 1.34 mmol, 1.00 equiv) in dichloromethane (40 mL),triethylamine (884 mg, 8.74 mmol, 5.00 equiv), 4-dimethylaminopyridine(43 mg, 0.35 mmol, 0.30 equiv), and 4-fluorobenzene-1-sulfonyl chloride(683 mg, 3.51 mmol, 2.60 equiv) was stirred for 2 h at room temperature.The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (35:100) to afford thetitle compound (328.3 mg, 47%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.47 (s, 1H), 9.30-9.29 (m, 1H), 8.94-8.90 (m,1H), 8.80-8.77 (m, 1H), 8.26-8.25 (m, 1H), 8.10-8.01 (m, 1H), 8.01-7.97(m, 2H), 7.57-7.51 (m, 2H), 4.52-4.48 (m, 2H), 3.60-3.54 (m, 1H),3.39-3.32 (m, 1H), 2.30-2.15 (m, 2H), 1.67-1.66 (m, 1H), 0.38-0.35 (m,1H), −0.41-−0.39 (m,1H).

Example 124: Preparation of(3R,6S)-1,1-difluoro-5-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-5-azaspiro[2.4]heptane-6-carboxamide.

Step 1: Preparation of 5-tert-butyl 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate

A mixture of NaI (87.14 mg, 0.50 equiv), 1-tert-butyl 2-methyl(2S)-4-methylidenepyrrolidine-1,2-dicarboxylate (280 mg, 1.16 mmol, 1.00equiv), and TMS-CF₃ (412.5 mg, 2.50 equiv) in tetrahydrofuran (10 mL)was stirred for 12 h at 60° C. under nitrogen. The reaction was thenquenched by saturated NH₄Cl solution. The resulting solution wasextracted with ethyl acetate, washed with saturated Na₂S₂O₃ and thenbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (400 mg, crude) as orangeoil.

Step 2: Preparation of(6S)-5-[(tert-butoxy)carbonyl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylicacid

A mixture of 5-tert-butyl 6-methyl(6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (400 mg, 1.37mmol, 1.00 equiv) and LiOH (164.95 mg, 6.89 mmol, 5.00 equiv) in water(5mL)/methanol (2 mL) was stirred for 2 h at 0-5° C. The mixture wasdiluted with water and extracted with ethyl acetate. The pH value of thewater layer was adjusted to 5 with hydrogen chloride (10%). Theresulting solution was extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (240 mg, 63%) as orange oil.

Step 3: Preparation of tert-butyl(6S)-1,1-difluoro-6-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]-5-azaspiro[2.4]heptane -5-carboxylate

A mixture of(6S)-5-[(tert-butoxy)carbonyl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylicacid (247 mg, 0.89 mmol, 1.00 equiv), HATU (508 mg, 1.34 mmol, 1.50equiv), DIEA (460.2 mg), and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (271.7 mg, 0.93 mmol, 1.20 equiv) in N,N-dimethylformamide(15 mL) was stirred for 1 h at room temperature. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:3) to afford the title compound(230 mg) as a light yellow solid.

Step 4: Preparation of(6S)-1,1-difluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-5-azaspiro[2.4]heptane-6-carboxamide

A mixture of tert-butyl(6S)-1,1-difluoro-6-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]-5-azaspiro[2.4]heptane-5-carboxylate(230 mg, 0.45 mmol, 1.00 equiv) and saturated hydrogen chloride indioxane (3 mL) was stirred for 12 h at room temperature. The resultingsolution was concentrated under vacuum to afford the title compound (200mg, crude) as an orange solid.

Step 5: Preparation of(3R,6S)-1,1-difluoro-5-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-5-azaspiro[2.4]heptane-6-carboxamide

A mixture of(6S)-1,1-difluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-5-azaspiro[2.4]heptane-6-carboxamidehydrochloride (200 mg, 0.44 mmol, 1.00 equiv), triethylamine (179.78 mg,1.78 mmol, 4.00 equiv), 4-fluorobenzene-1-sulfonyl chloride (103.7 mg,0.53 mmol, 1.20 equiv), and 4-dimethylaminopyridine (5.43 mg, 0.04 mmol,0.10 equiv) in dichloromethane (10 mL) was stirred for 12 h at roomtemperature. The reaction was then quenched by water and extracted withethyl acetate. The organic layers were combined, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thecrude product was purified by Prep-HPLC to afford the title compound(42.7 mg, 17%) as a white solid. t_(R)=1.14 min (Repaired IC (CHIRALPAKIC), 0.46×10 cm, 5 μm, MeOH (0.1% DEA)=2%, 4 ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.48 (s, 1H), 9.29 (s, 1H), 8.70-8.67 (m, 1H),8.03 (s, 1H), 7.96-7.91 (m, 2H), 7.91-7.84 (m, 1H), 7.75-7.71 (m, 1H),7.34-7.26 (m, 2H), 4.99-4.91 (m, 1H), 4.64-4.56 (m, 1H), 4.39-4.34 (m,1H), 3.61 (s, 2H), 2.25-2.01 (m, 2H), 1.40-1.34 (m, 2H).

And(3S,6S)-1,1-difluoro-5-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)-5-azaspiro[2.4]heptane-6-carboxamidewas also isolated (27.3 mg, 11%) as a white solid. t_(R)=1.45 min(Repaired IC (CHIRALPAK IC), 0.46×10 cm, 5 μm, MeOH (0.1% DEA)=2%, 4ml/min).

¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 9.30 (s, 1H), 8.99 (m, 1H),8.79-8.77 (d, J=6 Hz, 1H), 8.15-8.03 (m, 4H), 7.53-7.47 (m, 2H),4.53-4.45 (m, 3H), 3.61-3.32 (m, 2H), 2.03 (s, 2H), 1.48-1.44 (m, 2H).

The stereochemistry for position 4 of the prolines was arbitrarilyassigned. The stereochemistry for position 2 of the prolines is asshown.

Example 125 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-2-methylpyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-2-methylpyrrolidine-2-carboxamide

A mixture of(2R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (360 mg, 1.18 mmol, 1.00 equiv), HATU (673 mg, 1.77 mmol, 1.50equiv), DIEA (456 mg, 3.53 mmol, 3.00 equiv), and[3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine(250 mg, 0.92 mmol, 0.80 equiv) in N,N-dimethylformamide (15 mL) wasstirred for 3 h at room temperature. The reaction was then quenched bywater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:5). The crude product was purifiedby Chiral-Prep-HPLC to afford the title compound (39.8 mg, 6%) as awhite solid. t_(R)=2.42 min (Lux 3 μm, Cellulose-4, 0.46×5 cm, 3 μm,Hex:EtOH=70:30, 1.0 ml/min).

¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.06-8.04 (m, 2H), 7.93-7.89 (m,2H), 7.70-7.68 (d, J=6.0 Hz, 1H), 7.24-7.17 (m, 2H), 7.05 (s, 1H),5.23-5.05 (m, 1H), 4.45-4.25 (m, 2H), 4.04 (s, 3H), 3.91-3.63 (m, 2H),2.77-2.58 (m. 1H), 2.33-2.27 (m, 1H), 1.70 (s, 3H).

(2R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-2-methylpyrrolidine-2-carboxamidewas also isolated (110 mg, 17%) as a white solid. t_(R)=3.56 min (Lux 3μm, Cellulose-4, 0.46×5 cm, 3 μm, Hex:EtOH=70:30, 1.0 ml/min).

¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.07-8.02 (m, 2H), 7.91-7.86 (m,2H), 7.70-7.67 (d, J=6 Hz, 1H), 7.26-7.20 (m, 3H), 5.22-5.03 (m, 1H),4.48-4.24 (m, 2H), 4.07-3.96 (m, 4H), 3.52-3.36 (m, 1H), 2.95-2.83 (m,1H), 2.05-1.86 (m, 1H), 1.64 (s, 3H).

Example 126 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of(2R,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-4-[6-(trifluoromethyl)-3-pyridyl]-2-pyridyl]methyl]-2-methyl-pyrrolidine-2-carboxamide

A mixture of[5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(100.00 mg, 0.37 mmol, 1.00 equiv),(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (112.57 mg, 0.37 mmol, 1.00 equiv), HOBT (54.80 mg, 0.41 mmol, 1.10equiv), EDCI (141.37 mg, 0.74 mmol, 2.00 equiv), and DIEA (95.31 mg,0.74 mmol, 2.00 equiv) in THF (5 mL) was stirred for 12 h at 25° C. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The crude product (100.9 mg) was purified by Prep-HPLC toafford(2S,4R)-4-fluoro-N-([5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxamide(41.9 mg, 20%) as a white solid. t_(R)=1.68 min (CHIRALPAK AD-H, 0.46×15cm, 5 μm, MeOH (0.1% DEA)=30%, 4 ml/min).

¹H NMR (400 MHz, CD₃OD) δ 9.06 (s, 1H), 8.60-8.59 (d, J=4 Hz,1H),8.42-8.40 (m, 1H), 8.03-7.96 (m, 3H), 7.88-7.87 (d, J=4 Hz, 1H),7.39-7.35 (m, 2H), 5.36-5.18 (d, J=72 Hz, 1H), 4.79-4.75 (d, J=16 Hz,1H), 4.58-4.54 (d, J=16 Hz, 1H), 4.18-4.05 (m, 1H), 3.83-3.62 (m, 1H),2.78-2.62 (m, 1H), 2.13-2.28 (m, 1H), 1.60(s, 3H).

(2R,4R)-4-fluoro-N-([5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxamide(20.9 mg, 10%) was also isolated from the reaction as a white solid.t_(R)=2.12 min (CHIRALPAK AD-H, 0.46×15 cm, 5 μm, MeOH (0.1% DEA)=30%, 4ml/min).

¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.60-8.59 (d, J=4 Hz, 1H),8.41-8.39 (d,J=8 Hz, 1H), 7.98-7.90 (m, 4H), 7.32-7.27 (m, 2H),5.35-5.34 (d, J=4 Hz, 1H), 4.89-4.58 (m, 2H), 3.92-3.76 (m, 2H),2.70-2.32 (m, 2H), 1.78 (s, 1H).

Example 127 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([2-methoxy-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of[2-(benzylsulfanyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride

A mixture of tert-butylN-[[2-(benzylsulfanyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]carbamate(1.2 g, 2.52 mmol, 1.00 equiv) and saturated HCl in 50 mL of 1,4-dioxanewas stirred for 3 h at room temperature. The solids were collected byfiltration to afford the title compound (850 mg, 82%) as a gray solid.

Step 2: Preparation of(1S,4R)-N-[[2-(benzylsulfanyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]-4-fluoro-2-[(4-fluorobenzene)sulfonyl]cyclopentane-1-carboxamidehydrochloride

A solution of(1S,4R)-4-fluoro-2-[(4-fluorobenzene)sulfonyl]cyclopentane-1-carboxylicacid (300 mg, 1.03 mmol, 1.00 equiv), HATU (470 mg, 1.24 mmol, 1.00equiv), and DIEA (266 mg, 2.06 mmol, 2.00 equiv) inN,N-dimethylformamide (8 mL) was stirred for 10 min at room temperature.[2-(Benzylsulfanyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (424 mg, 1.03 mmol, 1.00 equiv) was added and theresulting solution was stirred overnight at room temperature. Theresulting solution was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:1). This resulted in the title compound (320mg, 48%) as light brown oil.

Step 3: Preparation of(1S,4R)-4-fluoro-2-[(4-fluorobenzene)sulfonyl]-N-[[2-(phenylmethane)sulfonyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]cyclopentane-1-carboxamide

m-CPBA (340 mg, 1.97 mmol, 4.00 equiv) was added in portions into asolution of(1S,4R)-N-[[2-(benzylsulfanyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]-4-fluoro-2-[(4-fluorobenzene)sulfonyl]cyclopentane-1-carboxamide(320 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (50 mL) at roomtemperature. After 4 h at room temperature the resulting solution wasdiluted with dichloromethane, washed with saturated sodium bicarbonate,dried over sodium sulfate, and concentrated under vacuum. The residuewas purified by a silica gel column eluting with ethyl acetate/petroleumether (2:1) to afford the title compound (250 mg, 74%) as a yellowsolid.

Step 4: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([2-methoxy-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

Sodium methylate (60 mg, 2.00 equiv) was added in several batches into asolution of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-[[2-(phenylmethane)sulfonyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide(250 mg, 0.37 mmol, 1.00 equiv) in methanol (20 mL) at 0° C. Theresulting solution was stirred for 30 min at room temperature andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (2:1) to afford thetitle compound (91.7 mg, 45%) as a pink solid.

¹H NMR (300MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.10 (t, J=5.8 Hz, 1H), 8.78(d, J=8.4 Hz, 1H), 8.09-8.00 (m, 3H), 7.88 (s, 1H), 7.47 (t, J=8.8 Hz,2H), 5.29-5.12 (d, J=52.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H), 4.27-4.22(dd, J=9.9 Hz, J=7.2 Hz, 1H), 4.04 (s, 3H), 3.75 (s, 1H), 3.71-3.58 (m,1H), 2.51-2.37 (m, 1H), 2.24-2.01 (m, 1H).

Example 128 Preparation of(2S,4R)-N-[[4-(4,4-difluoro-1-piperidyl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of tert-butyl 4,4-difluoropiperidine-1-carboxylate

BAST (222.4 g, 1.01 mol, 20.00 equiv) was added dropwise into a solutionof tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.19 mmol, 1.00equiv) in dichloromethane (200 mL) at 0° C. under nitrogen. Theresulting solution was stirred overnight at 25° C. The reaction was thenquenched by saturated sodium bicarbonate, extracted withdichloromethane, washed with brine, dried over sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/10). This resultedin the title compound (9.7 g, 87%) as a light yellow solid.

Step 2: Preparation of 4,4-difluoropiperidine hydrochloride

A mixture of tert-butyl 4,4-difluoropiperidine-1-carboxylate (5 g, 22.60mmol, 1.00 equiv) and hydrogen chloride (saturated solution in 150 mL of1,4-dioxane) was stirred for 6 h at 25° C. The resulting mixture wasconcentrated under vacuum to afford the title compound (4.2 g, crude) asa yellow solid.

Step 3: Preparation of2-chloro-4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine

A mixture of 2-chloro-5-fluoro-4-iodopyridine (813 mg, 3.16 mmol, 1.00equiv), 4,4-difluoropiperidine hydrochloride (500 mg, 3.17 mmol, 1.00equiv), XantPhos (183 mg, 0.32 mmol, 0.10 equiv), Cs₂CO₃ (3.1 g, 9.51mmol, 3.00 equiv), and Pd₂(dba)₃CHCl₃ (164 mg, 0.16 mmol, 0.05 equiv) intoluene (20 mL) was stirred overnight at 100° C. under nitrogen. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/5) to afford the title compound (200 mg, 25%)as a yellow solid.

Step 4: Preparation of4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-2-carbonitrile

A mixture of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine(150 mg, 0.60 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (10.3 mg, 0.01 mmol,0.05 equiv), Zn(CN)₂ (23.3 mg, 0.20 mmol, 1.00 equiv), dppf (11 mg, 0.02mmol, 0.10 equiv), Zn (1.3 mg, 0.02 mmol, 0.10 equiv), and DMA (2 mL)was irradiated with microwave radiation for 1.5 h at 125° C. undernitrogen. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/4) to afford thetitle compound (180 mg) as a yellow solid.

Step 5: [4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]methanaminehydrochloride

A mixture of4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridine-2-carbonitrile (180 mg,0.75 mmol, 1.00 equiv), methanol (20 mL), palladium on carbon (180 mg,1.69 mmol, 1.00 equiv), and concentrated hydrogen chloride (0.2 mL) wasstirred for 20 min at 25° C. under hydrogen. The solids were filteredout. The resulting solution was concentrated under vacuum to afford thetitle compound (180 mg, 98%) as a white solid.

Step 6: Preparation of(2S,4R)-N-[[4-(4,4-difluoro-1-piperidyl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of[4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl]methanaminehydrochloride (180 mg, 0.73 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (213.8 mg, 0.73 mmol, 1.00 equiv), EDCI (282.1 mg, 1.47 mmol, 2.00equiv), HOBt (109.1 mg, 0.81 mmol, 1.10 equiv), and DIEA (189.6 mg, 1.47mmol, 12.00 equiv) in tetrahydrofuran (10 mL) was stirred overnight at25° C. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The crude product (150 mg) was purified byPrep-HPLC to afford the title compound (39.2 mg, 10%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.09-8.01 (m, 1H), 8.00-7.97 (m, 2H),7.38-7.32 (m, 2H), 7.19-7.17 (m, 1H), 5.21-5.14 (d, J=52.0 Hz, 1H),4.52-4.39 (m, 2H), 4.27-4.21 (m, 1H), 3.83-3.74 (m, 2H), 3.70-3.54 (m,4H), 2.62-2.42 (m, 1H), 2.27-2.00 (m, 5H).

Example 129: Preparation of(2S,4R)-N-[[4-(6-azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of6-(2-chloro-5-fluoropyridin-4-yl)-6-azaspiro[2.5]octane

A mixture of 6-azaspiro[2.5]octane hydrochloride (1.00 g, 6.77 mmol,1.00 equiv), 2-chloro-5-fluoro-4-iodopyridine (1.74 g, 6.76 mmol, 1.00equiv), Pd₂(dba)₃.CHCl₃ (350 mg, 0.34 mmol, 0.05 equiv), BINAP (420 mg,0.67 mmol, 0.10 equiv), and t-BuONa (1.95 g, 20.29 mmol, 3.00 equiv) intoluene (20 mL) was stirred for overnight at 100° C. under nitrogen. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1/10) to afford the title compound(480 mg, 29%) as a light yellow solid.

Step 2: Preparation of4-(4-cyclopropylpiperidin-1-yl)-5-fluoropyridine-2-carbonitrile

A mixture of 2-chloro-4-(4-cyclopropylpiperidin-1-yl)-5-fluoropyridine(480.00 mg, 1.88 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (103 mg, 0.10 mmol,0.05 equiv), Zn(CN)₂ (140 mg, 1.19 mmol, 0.60 equiv), dppf (104.46 mg,0.19 mmol, 0.10 equiv), Zn (12.33 mg, 0.19 mmol, 0.10 equiv), and DMA (5mL, 53.78 mmol, 28.50 equiv) was irradiated with microwave radiation for1 h at 100° C. under nitrogen. The reaction mixture was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/10) to afford the title compound (170 mg, 37%) as a lightyellow solid.

Step 3: Preparation of(4-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridin-2-yl)methanaminehydrochloride

A mixture of4-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridine-2-carbonitrile (140 mg,0.61 mmol, 1.00 equiv), methanol (5 mL, 123.49 mmol, 204.00 equiv),palladium on carbon (140 mg, 1.32 mmol, 2.20 equiv), and concentratedhydrogen chloride (0.1 mL) was stirred for 15 min at 25° C. underhydrogen. The resulting mixture was concentrated under vacuum to affordthe title compound (140 mg, 98%) as a light yellow solid.

Step 4: Preparation of(2S,4R)-N-[[4-(6-azaspiro[2.5]octan-6-yl)-5-fluoro-2-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(4-[6-azaspiro[2.5]octan-6-yl]-5-fluoropyridin-2-yl)methanamine (140.00mg, 0.59 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (225.29 mg, 0.77 mmol, 1.30 equiv), EDCI (228.12 mg, 1.19 mmol,2.00 equiv), HOBT (88.44 mg, 0.65 mmol, 1.10 equiv), and DIEA (153.80mg, 1.19 mmol, 2.00 equiv) in THF (5 mL) was stirred overnight at 25° C.The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The crude product (43.9 mg) was purified byPrep-HPLC to afford the title compound (28.4 mg, 9%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.04-7.98 (m, 3H), 7.38-7.33 (m, 2H),7.16-7.14 (d, J=8 Hz, 1H), 5.20-5.07(d, J=52 Hz, 1H), 4.46 (s, 2H),4.28-4.24 (m, 1H), 3.83-3.68 (m, 2H), 3.49-3.46 (m, 4H), 2.54-2.46 (m,1H), 2.26-2.12 (m, 1H),1.51-1.49 (m, 4H), 0.37 (s, 4H).

Example 130 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-(trifluoromethyl)-4-[4-(trifluoromethyl)-1-piperidyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of2-chloro-5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine

A mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.00 g, 3.25mmol, 1.00 equiv), 4-(trifluoromethyl)piperidine (500 mg, 3.26 mmol,1.00 equiv), Pd(dppf)Cl₂.CH₂Cl₂(130 mg, 0.16 mmol, 0.05 equiv), andCs₂CO₃ (2.12 g, 6.51 mmol, 2.00 equiv) in toluene (10.00 mL) was stirredovernight at 100° C. under nitrogen. The reaction mixture was dilutedwith water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/10) to afford the title compound (700 mg, 65%) as a yellowsolid.

Step 2: Preparation of5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine-2-carbonitrile

A mixture of2-chloro-5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine(700.00 mg, 2.10 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (108.90 mg, 0.11mmol, 0.05 equiv), Zn(CN)₂ (148.27 mg, 1.26 mmol, 0.60 equiv), dppf(116.65 mg, 0.21 mmol, 0.10 equiv), Zn (13.76 mg, 0.21 mmol, 0.10equiv), and DMA (5.01 mL) was irradiated with microwave radiation for 1h at 125° C. under nitrogen. The reaction mixture was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/10) to afford the title compound (450 mg, 66%) as a whitesolid.

Step 3: Preparation of[5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine-2-carbonitrile(120 mg, 0.37 mmol, 1.00 equiv), palladium on carbon (120 mg, 1.13 mmol,3.00 equiv), and concentrated hydrogen chloride (0.1 mL) in methanol (10mL) was stirred for 10 min at 25° C. under hydrogen. The resultingmixture was concentrated under vacuum to afford the title compound (130mg, crude) as a white solid.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-(trifluoromethyl)-4-[4-(trifluoromethyl)-1-piperidyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of[5-(trifluoromethyl)-4-[4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]methanamine(100.00 mg, 0.31 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (115.70 mg, 0.40 mmol, 1.30 equiv), EDCI (117.15 mg, 0.61 mmol,2.00 equiv), HOBT (45.42 mg, 0.34 mmol, 1.10 equiv), and DIEA (78.98 mg,0.61 mmol, 2.00 equiv) in tetrahydrofuran (5 mL) was stirred overnightat 25° C. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The crude product (58 mg) was purified byPrep-HPLC to afford the title compound (43.4 mg, 24%) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s,1H), 8.05-8.00 (m, 2H), 7.40-7.35 (m,3H), 5.24-5.18 (d, J=18 Hz, 2H), 4.57-4.56 (m, 2H), 4.31-4.26 (m, 1H),3.86 (s, 1H), 3.68-3.63 (m, 3H), 3.02 (m, 2H), 2.68-2.12 (m, 3H),1.97-1.93 (d, J=12 Hz, 2H), 1.73-1.72 (m, 2H).

Example 131 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile

A mixture of 4-chloropyridine-2-carbonitrile (5 g, 36.09 mmol, 1.00equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (13.8 g, 54.34 mmol, 1.50 equiv), KOAc (11 g, 112.08mmol, 3.10 equiv), and Pd(dppf)Cl₂ (1.33 g, 1.82 mmol) in dioxane (40mL) was stirred for 6 h at 100° C. under nitrogen. The reaction mixturewas diluted with water, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (16 g, crude) as black oil.

Step 2: Preparation of4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2-carbonitrile

A mixture of4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (1.6 g,6.95 mmol, 3.10 equiv), 2-bromo-5-(trifluoromethyl)pyridine (500 mg,2.21 mmol, 1.00 equiv), Pd(dppf)Cl₂ (170 mg, 0.23 mmol, 0.10 equiv), andpotassium carbonate (921 mg, 6.66 mmol, 3.00 equiv) in dioxane (40mL)/water (2 mL) was stirred for 12 h at 100° C. under nitrogen. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:20) to afford the title compound(380 mg, 69%) as a white solid.

Step 3: Preparation of[4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of 4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2-carbonitrile(200 mg, 0.80 mmol, 1.00 equiv), palladium on carbon (100 mg, 0.94 mmol,1.20 equiv), and concentrated hydrogen chloride (0.1 mL) in ethanol (10mL) was stirred for 30 min at room temperature under hydrogen. Thesolids were filtered out. The filtrate was concentrated under vacuum toafford the title compound (240 mg, crude) as a white solid.

Step4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[5-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (150.00 mg, 0.51 mmol, 1.00 equiv), DIEA (266.23 mg, 2.06 mmol,4.00 equiv), HATU (293.72 mg, 0.77 mmol, 1.50 equiv), and[4-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-yl]methanaminehydrochloride (223.77 mg, 0.77 mmol, 1.50 equiv) inN,N-dimethylformamide (5 mL) was stirred for 12 h at room temperature.The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with dichloromethane/methanol (20:1) to afford the titlecompound (78.2 mg, 29%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 9.02-9.01 (m, 1H), 8.71 (d,J=4.8 Hz, 1H), 8.83-8.22 (m, 2H), 8.09-7.98 (m, 4H), 7.47-7.43 (m, 2H),5.21 (d, J=52.8 Hz, 2H), 4.53-4.24 (m, 3H), 3.76-3.58 (m, 2H), 2.50-2.33(m, 1H), 2.22-2.04 (m, 1H).

Example 132 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 5-bromo-2-(trifluoromethyl)pyrimidine

A mixture of 5-bromo-2-iodopyrimidine (10 g, 35.10 mmol, 1.00 equiv),trimethyl(trifluoromethyl)silane (20 g, 140.65 mmol, 4.00 equiv), KF(4.1 g, 70.57 mmol, 2.00 equiv), and CuI (13 g, 68.26 mmol, 2.00 equiv)in NMP (80 mL) was stirred overnight at 70° C. under nitrogen. Thereaction was quenched by 200 mL of ammonia hydroxide, extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith petroleum ether to afford the title compound 1.1 g (14%) of5-bromo-2-(trifluoromethyl)pyrimidine as a light yellow solid.

Step 2: Preparation of ethyl3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carboxylate

A mixture of CuI (88 mg, 0.46 mmol, 0.10 equiv), L-proline (108 mg, 0.94mmol, 0.20 equiv), potassium carbonate (1.3 g, 9.41 mmol, 2.00 equiv),ethyl 3-methoxy-1H-pyrazole-4-carboxylate (800 mg, 4.70 mmol, 1.00equiv), and 5-bromo-2-(trifluoromethyl)pyrimidine (1.28 g, 5.64 mmol,1.20 equiv) in DMSO (5 mL) was stirred overnight at 100° C. undernitrogen. The reaction mixture was diluted with 40 mL of water,extracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:5) to afford thetitle compound (580 mg, 39%) as a white solid.

Step 3: Preparation of3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carboxylicacid

A mixture of ethyl3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carboxylate(150 mg, 0.47 mmol, 1.0 equiv) and LiOH (22 mg, 0.92 mmol, 2.0 equiv) inTHF (5 mL)/water (2 mL) was stirred for 2 h at 50° C. and diluted with30 mL of water. The pH value of the solution was adjusted to 2 withdiluted HCl. The resulting solution was extracted with ethyl acetate,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (120 mg, 88%) as a white solid.

Step 4: Preparation of3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carboxamide

A mixture of3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carboxylicacid (400 mg, 1.39 mmol, 1.0 equiv), HATU (792 mg, 2.08 mmol, 1.5equiv), DIEA (540 mg, 4.18 mmol, 3.0 equiv), and NH₄Cl (110 mg, 2.06mmol, 1.5 equiv) in N,N-dimethylformamide (20 ml) was stirred for 1 h atroom temperature. The reaction was diluted with 30 mL of water,extracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3). This resultedin the title compound (300 mg, 75%) as a white solid.

Step 5: Preparation of3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbonitrile

A mixture of3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (300mg, 1.05 mmol, 1.00 equiv), pyridine (347 mg, 4.39 mmol, 4.00 equiv),and Tf₂O (620 mg, 2.20 mmol, 2.00 equiv) in dichloromethane (30 mL) wasstirred for 2 h at room temperature. The reaction was diluted with 30 mLof water, extracted with dichloromethane, dried over anhydrous sodiumsulfate, and concentrated under vacuum. This resulted in the titlecompound 170 mg (60%) as a brown solid.

Step 6: Preparation of(3-methoxy-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of H₂ was placed3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazole-4-carbonitri le (170 mg, 0.63 mmol, 1.00 equiv), methanol (30 mL),hydrogen chloride (0.5 mL, 13.71 mmol, 1.00 equiv), and palladium oncarbon (40 mg, 0.38 mmol, 1.00 equiv). After 30 min at room temperaturethe solids were filtered out. The liquid was concentrated under vacuumto afford the title compound (120 mg, 70%) of as a light yellow solid.

Step 7: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (253 mg, 0.87 mmol, 1.50 equiv), HATU (330 mg, 0.87 mmol, 1.50equiv), and DIEA (224 mg, 1.73 mmol, 3.00 equiv) inN,N-dimethylformamide (3 mL) was stirred for 15 min at room temperatureand then(3-methoxy-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-4-yl)methanaminehydrochloride (160 mg, 0.59 mmol, 1.0 equiv) was added. The resultingsolution was stirred overnight at room temperature, diluted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate, andconcentrated under vacuum. The crude product was purified by Pre-HPLC toafford the title compound 20 mg (6%) of as a white solid

¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 8.65-8.62 (m, 1H), 8.48 (s, 1H),7.97-7.79 (m, 2H), 7.47-7.42 (m, 2H), 5.24-5.11 (d, J=52.4 Hz, 1H),4.18-4.05 (m, 3H), 3.99 (s, 3H), 3.69-3.58 (m, 2H), 2.40-2.22 (m, 1H),2.18-1.95 (m, 1H).

Example 133 Preparation of(2S,4R)-N-[[6-[4-(difluoromethyl)-1-bicyclo[2.2.2]octanyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Step 1: Preparation of methyl4-[2-acetyl-3-(tert-butoxy)-3-oxopropanoyl]bicyclo[2.2.2]octane-1-carboxylate

PrMgBr (71 mL, 575.75 mmol, 1M in THF, 1.50 equiv) was added dropwiseinto a solution of tert-butyl 3-oxobutanoate (11.2 g, 70.80 mmol, 1.50equiv) in tetrahydrofuran (150 mL) at 0° C. under nitrogen. After 2 h at0° C. the chloride (prepared by refluxing4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (10 g, 47.12mmol, 1.00 equiv) in thionyl chloride (50 mL) for 3 h) in 50 mL of THFat 0° C. The resulting solution was stirred for 12 h at roomtemperature. The reaction was then quenched by saturated solution ofNH₄Cl, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (10 g, crude) as yellow oil.

Step 2: Preparation of methyl4-(3-oxobutanoyl)bicyclo[2.2.2]octane-1-carboxylate

A solution of methyl4-[2-acetyl-3-(tert-butoxy)-3-oxopropanoyl]bicyclo[2.2.2]octane-1-carboxylate(10 g, 28.38 mmol, 1.00 equiv) and 2,2,2-trifluoroacetaldehyde (20 mL)in DCM (100 mL) was stirred for 12 h at room temperature. The pH valueof the solution was adjusted to 8 to 9 with sodium bicarbonate. Theresulting solution was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/10) to afford thetitle compound (4.8 g, 67%) as a light yellow solid.

Step3: Preparation of methyl4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate

A solution of methyl 4-(3-oxobutanoyl)bicyclo[2.2.2]octane-1-carboxylate(4.8 g, 19.02 mmol, 1.00 equiv) in formamide (50 mL) was irradiated withmicrowave radiation for 3 h at 180° C. in 5 batches. The reactionmixture was diluted with water, extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1/20) to afford the title compound (1.5g, 30%) as a light yellow solid.

Step4: Preparation of[4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octan-1-yl]methanol

DIBAL-H (17 mL, 119.53 mmol, 1M in hexanes, 3.00 equiv) was addeddropwise into a solution of methyl4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (1.5 g,5.76 mmol, 1.00 equiv) in dichloromethane (150 mL) at −78° C. undernitrogen. The resulting solution was stirred for 3 h at −78° C. Thereaction was then quenched by sodium hydroxide (1N). The solids werefiltered out. The filtrate was dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in the title compound (1.1 g,82%) as a white solid.

Step 5: Preparation of4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carbaldehyde

A mixture of[4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octan-1-yl]methanol (1.1 g,4.73 mmol, 1.00 equiv) and DMP (2.0 g, 4.72 mmol, 1.00 equiv) indichloromethane (150 mL) was stirred for 1 h at room temperature. Thesolids were filtered out. The resulting solution was diluted withCH₂Cl₂, washed with saturated sodium bicarbonate and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/10) to afford the title compound (875 mg, 80%) as a lightyellow solid.

Step 6: Preparation of4-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]-6-methylpyrimidine

DAST (8.67 g, 37.86 mmol, 10.00 equiv) was added dropwise into asolution of4-(6-methylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carbaldehyde (875 mg,3.80 mmol, 1.00 equiv) in dichloromethane (200 mL) at −78° C. undernitrogen. The resulting solution was stirred for 12 h at roomtemperature. The reaction was then quenched by saturated sodiumbicarbonate and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1/4) to afford the title compound(750 mg, 78%) as a light yellow solid.

Step 7: Preparation of4-(bromomethyl)-6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidine

BPO (152 mg, 0.59 mmol, 0.20 equiv) was added in portions into a mixtureof 4-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]-6-methylpyrimidine(750 mg, 2.97 mmol, 1.00 equiv) and NBS (530 mg, 2.98 mmol, 1.00 equiv)in CCl₄ (50 mL) at room temperature under nitrogen. The resultingsolution was heated to 80° C. After 6 h at 80° C. the reaction mixturewas cooled to room temperature. The reaction mixture was then dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in the title compound (750 mg, crude) asyellow oil.

Step 8: Preparation of2-([6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

A mixture of4-(bromomethyl)-6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidine(550 mg, 1.66 mmol, 1.00 equiv) and2-potassio-2,3-dihydro-1H-isoindole-1,3-dione (307 mg, 1.66 mmol, 1.00equiv) in N,N-dimethylformamide (5 mL) was stirred for 12 h at roomtemperature. The reaction mixture was diluted with water and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/1) to afford the title compound (180 mg) asan off-white solid.

Step 9: Preparation of[6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidin-4-yl]methanamine

A mixture of2-([6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(180 mg, 0.45 mmol, 1.00 equiv) and hydrazine hydrate (227 mg, 4.53mmol, 10.00 equiv) in methanol (10 mL) was stirred for 12 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was dissolved in ethyl acetate. The solids were filtered out andthe filtrate was concentrated under vacuum. This resulted in the titlecompound (100 mg, 83%) as a yellow solid which was used for the nextstep without any further purification.

Step 10: Preparation of (2S,4R)-N-[[6-[4-(difluoromethyl)-1-bicyclo[2.2.2]octanyl]pyrimidin-4-yl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (218 mg, 0.75 mmol, 2.00 equiv), DIEA (145 mg, 1.12 mmol, 3.00equiv), HATU (285 mg, 0.75 mmol, 2.00 equiv), and[6-[4-(difluoromethyl)bicyclo[2.2.2]octan-1-yl]pyrimidin-4-yl]methanamine(100 mg, 0.37 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) wasstirred for 1 h at room temperature. The reaction mixture was dilutedwith water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC to afford the title compound (38.7 mg,19%) as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.95 (s, 1H), 8.04-8.00 (m, 2H), 7.72 (s, 1H),7.39-7.34 (m, 2H), 5.67-5.29 (t, J=56.9 Hz, 1H), 5.23-5.05 (d, J=52.2Hz, 1H), 4.59-4.46 (m, 2H), 4.28-4.25 (m, 1H), 3.84-3.70 (m, 2H),2.52-2.11 (m, 2H), 2.04-1.94 (m, 6H), 1.68-1.63 (m, 6H).

Example 134 Preparation of(2S,4R)-4-fluoro-1-[(3-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-4-fluoro-1-[(3-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(1S,4R)-4-fluoro-2-[(3-fluorobenzene)sulfonyl]cyclopentane-1-carboxylicacid (384 mg, 1.32 mmol, 1.50 equiv), HATU (501 mg, 1.32 mmol, 1.50equiv), DIEA (227 mg, 1.76 mmol, 2.00 equiv), and[3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine(240 mg, 0.88 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) wasstirred overnight at room temperature. The mixture was diluted withwater, extracted with ethyl acetate. The combined extracts were washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The crude product was purified by Prep-HPLC to afford the titlecompound (60.4 mg, 13%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.62-8.61 (m, 1H), 8.36 (s, 1H), 7.88-7.54(m, 8H), 5.25-5.12 (d, J=52.4 Hz, 1H), 4.21-4.05 (m, 3H), 3.96 (s, 3H),3.76-3.54 (m, 2H), 2.37-2.29 (m, 1H), 2.15-1.95 (m, 1H).

Example 135 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-butyl 4-ethyl3-hydroxy-1H-pyrazole-1,4-dicarboxylate

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (15 g, 96.07mmol, 1.00 equiv), 4-dimethylaminopyridine (587 mg, 4.80 mmol, 0.05equiv), triethylamine (29 g, 286.59 mmol, 3.00 equiv), and Boc₂O (42 g,192.4 mmol, 2.0 equiv) in tetrahydrofuran (180 mL) was stirred overnightat room temperature and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:3) to afford the title compound (20 g, 81%) as a white solid.

Step 2: Preparation of 1-tert-butyl 4-ethyl3-methoxy-1H-pyrazole-1,4-dicarboxylate

Into a 250-mL round-bottom flask was placed 1-tert-butyl 4-ethyl3-hydroxy-1H-pyrazole-1,4-dicarboxylate (1.8 g, 7.02 mmol, 1.00 equiv),CH₃CN (60 mL, 1.14 mol, 100.00 equiv), and potassium carbonate (3.86 g,27.93 mmol, 4.00 equiv). Iodomethane (3.0 g, 21.14 mmol, 3.0 equiv) wasadded dropwise at 0° C. After 3 h at room temperature the solid wasfiltered out. The liquid was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:1) to afford the title compound (600 mg, 32%) as colorless oil.

Step 3: Preparation of ethyl 3-methoxy-1H-pyrazole-4-carboxylate

A mixture of 1-tert-butyl 4-ethyl3-methoxy-1H-pyrazole-1,4-dicarboxylate (16 g, 59.20 mmol, 1.00 equiv)and saturated hydrogen chloride in 1,4-dioxane (200 mL) was stirred for5 h at room temperature and concentrated under vacuum. The resultingsolution was diluted with 20 mL of water and the pH value of thesolution was adjusted to 8 by sodium bicarbonate. The resulting solutionwas extracted with ethyl acetate, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (7 g,69%) as brown oil.

Step 4: Preparation of ethyl3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylate

A mixture of CuI (95 mg, 0.50 mmol, 0.10 equiv), L-proline (115 mg, 1.00mmol, 0.20 equiv), potassium carbonate (1.38 g, 9.99 mmol, 2.00 equiv),ethyl 3-methoxy-1H-pyrazole-4-carboxylate (850 mg, 5.00 mmol, 1.00equiv), and 1-bromo-4-(trifluoromethyl)benzene (2.04 g, 7.50 mmol, 1.50equiv) in DMSO (10 mL) was stirred overnight at 100° C. under nitrogen.The reaction was diluted with water, extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in the title compound (1.06 g, 68%) as a white solid.

Step 5: Preparation of[3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanol

LiAlH₄ (385 mg, 10.14 mmol, 3.0 equiv) was added batch wise into asolution of ethyl3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylate (1.06g, 3.37 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) at 0° C. undernitrogen. The resulting solution was stirred for 1.5 h at 0° C.,quenched by water, extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under vacuum. This resulted in thetitle compound (800 mg, 87%) as a light yellow solid.

Step 6: Preparation of3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde

A solution of[3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanol (580mg, 2.13 mmol, 1.00 equiv) and PCC (916 mg, 4.25 mmol, 2.0 equiv) indichloromethane (20 mL) was stirred for 3 h at room temperature andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3) to afford thetitle compound (500 mg, 87%) as a light yellow solid.

Step 7: Preparation of(E)-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methylidene)hydroxylamine

A mixture of3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde (500mg, 1.85 mmol, 1.00 equiv), hydroxylamine hydrochloride (383 mg, 5.51mmol, 3.00 equiv), and sodium acetate (759 mg, 9.25 mmol, 5.00 equiv) inethanol (20 mL) was stirred for 40 min at room temperature andconcentrated under vacuum. The residue was diluted with water, extractedwith ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (520 mg,99%) as a yellow solid.

Step 8: Preparation of[3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine

Into a 250-mL round-bottom flask purged and maintained with anatmosphere of H₂ was placed Raney Ni (50 mg, 0.58 mmol, 1.00 equiv),methanol (10 mL), and(E)-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methylidene)hydroxylamine(520 mg, 1.82 mmol, 1.00 equiv). After 30 min at room temperature thesolids were filtered out. The liquid was concentrated under vacuum toafford the title compound (480 mg) as a greenish solid.

Step 9: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (384 mg, 1.32 mmol, 1.50 equiv), HATU (501 mg, 1.32 mmol, 1.50equiv), DIEA (227 mg, 1.76 mmol, 2.00 equiv), and[3-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine(240 mg, 0.88 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL)wasstirred overnight at room temperature. The reaction was diluted with 20mL of water, extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:6). Thecrude product was purified by Prep-HPLC to afford the title compound(53.8 mg, 11%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.61-8.58 (m, 1H), 8.35 (s, 1H), 7.98-7.94 (m,2H), 7.87-7.80 (m, 4H), 7.47-7.42 (m, 2H), 5.24-5.11 (d, J=52.8 Hz, 1H),4.16-4.05 (m, 3H), 3.96 (s, 3H), 3.68-3.55 (m, 2H), 2.38-2.28 (m, 1H),2.15-1.90 (m, 1H).

Example 136 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: Preparation of tert-butyl(2S,3R)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

A mixture of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(200 mg, 0.86 mmol, 1.00 equiv), DMF (10 mL), HATU (493.6 mg, 1.30 mmol,1.50 equiv), DIEA (446.9 mg, 3.46 mmol, 4.00 equiv),[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (302.3 mg, 1.04 mmol, 1.20 equiv) was stirred for 3 h atroom temperature. The reaction was then quenched by the addition ofwater, extracted with ethyl acetate. The organic layers combined, washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated to afford the title compound 400 mg (99%) as orange oil.

Step 2: Preparation of tert-butyl(2R,3S)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate.

DAST (204 mg, 0.89 mmol, 3.00 equiv) was added dropwise into a solutionoftert-butyl(2S,3R)-3-hydroxy-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(200 mg, 0.43 mmol, 1.00 equiv) in 10 mL of DCM at 0° C. The resultingsolution was stirred for an additional 30 min at room temperature,quenched by the addition of water, extracted with ethyl acetate. Theorganic layers combined, dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (40:1) to afford the title compound 85 mg (42%)as a orange solid.

Step 3: Preparation of(2R,3S)-3-fluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2R,3S)-3-fluoro-2-[([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(85 mg, 0.18 mmol, 1.00 equiv), HCl in dioxane (10 mL, lmol/L) wasstirred for 3 h at room temperature. The resulting solution was dilutedwith ethyl acetate. The solids were collected by filtration to affordthe title compound 70 mg (95%) as a orange solid.

Step 4: Preparation of(2R,3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2R,3S)-3-fluoro-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (70 mg, 0.17 mmol, 1.00 equiv), TEA (51.5 mg, 0.51 mmol,3.00 equiv), 4-fluorobenzene-1-sulfonyl chloride (39.6 mg, 0.20 mmol,1.10 equiv), 4-dimethylaminopyridine (2.1 mg, 0.02 mmol, 0.10 equiv) inDCM (3 mL) was stirred for 3 h at room temperature. The reaction wasquenched by the addition of water, extracted with ethyl acetate. Theorganic layers combined, dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1) to afford the title compound 40 mg(44%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.49 (s, 1H),9.28 (s, 1H), 8.70-8.68 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.94-7.91 (m,2H), 7.84-7.80 (m, 2H), 7.31-7.27 (t, J=8.4 Hz, 2H), 5.38-5.26 (d, J=48Hz, 1H), 4.96-4.90 (m, 1H), 4.59-4.53 (m, 1H), 4.43-4.38 (d, J=22.4 Hz,1H), 3.86-3.81 (t, J=8.8 Hz 1H), 3.34-3.27 (m, 1H), 2.26-2.03 (m, 2H).

Example 137 Preparation of(2S,4R)-N-([3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-pyrrolidine-2-carboxylicacid (100 mg, 0.34 mmol), DMF (2 mL), DIPEA (132 mg, 1.02 mmol), HATU(194 mg, 0.51 mmol) and[3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine (187mg, 0.68 mmol) was stirred for 2 h at room temperature. The reactionmixture was purified directly by Prep-HPLC to afford the title compound(38 mg, 20%) as a white solid. ¹H NMR (400 MHz, CD₃OD)·8.45 (s, 1H),8.00-7.79 (m, 6H), 7.42-7.31 (m, 2H), 5.14 (d, J=52 Hz, 1H), 4.37 (s,2H), 4.30-4.19 (m, 1H), 3.87-3.69 (m, 3H), 2.52-2.43 (m, 1H), 2.25-2.08(m, 1H).

Example 138 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (125 mg, 0.41 mmol), DMF (4 mL), HATU (234 mg, 0.62 mmol), DIPEA(212 mg, 1.64 mmol) and[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]methanamine hydrochloride(106 mg, 0.37 mmol) was stirred for 12 h at room temperature. Themixture was diluted with water, extracted with EtOAc, washed with brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on silica gel eluting with EtOAc/petroleum ether(1:1).

Faster eluting isomer (24.8 mg) assigned by potency SAR as(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide:¹H NMR (300 MHz, CD₃OD) δ 9.19 (d, J=1.2 Hz, 1H), 8.45 (d, J=7.8 Hz,2H), 8.34 (s, 1H), 8.05-8.01 (m, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.32 (t,J=8.7 Hz, 2H), 5.30 (d, J=51.9 Hz, 1H), 4.71-4.51 (m, 2H), 3.94-3.90 (m,1H), 3.82 (d, J=2.4 Hz, 1H), 2.72-2.34 (m, 2H), 1.82 (s, 3H

Example 139(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of3-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile

A mixture of 3-bromo-5-fluorobenzonitrile (10 g, 50.00 mmol, 1.00equiv), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (9.6 g, 50.28mmol, 1.00 equiv), potassium carbonate (27.6 g, 199.70 mmol, 4.00equiv), and Pd(dppf)Cl₂ (3.67 g, 5.02 mmol, 0.10 equiv) in dioxane (400mL)/water(80 mL) was stirred overnight at 100° C. under nitrogen. Thereaction mixture was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (10:100) to afford the title compound(11.4 g, 86%) as a light yellow solid.

Step 2: Preparation of[3-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]phenyl]methanaminehydrochloride

A mixture of 3-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile (3g, 11.27 mmol, 1.00 equiv), palladium on carbon (1 g, 9.40 mmol, 0.80equiv), and concentrated HCl (10 mL) in methanol (200mL)/tetrahydrofuran (100 mL) was stirred for 1.5 h at room temperatureunder hydrogen. The solids were filtered out and the filtrate wasconcentrated under vacuum. This resulted in the title compound (4 g,crude) as a yellow solid.

Step3: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide

A mixture of[3-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]phenyl]methanaminehydrochloride (8 g, 26.09 mmol, 1.00 equiv),(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (7.6 g, 26.09 mmol, 1.00 equiv), DIEA (34 g, 263.07 mmol, 10.10equiv), and HATU (14.8 g, 38.92 mmol, 1.50 equiv) inN,N-dimethylformamide (300 mL) was stirred overnight at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (30:100) to afford thetitle compound (2.7672 g, 20%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.95-8.91 (m, 1H), 8.43-8.40(m, 1H), 8.01-7.95 (m, 3H), 7.66-7.62 (m, 2H), 7.50-7.43 (m, 2H),7.32-7.29 (m, 1H), 5.28-5.11 (m, 1H), 4.55-4.54 (m, 2H), 4.22-4.16 (m,1H), 3.73-3.60 (m, 2H), 2.42-2.37 (m, 1H), 2.16-2.02 (m, 1H).

Example 140 Preparation of(2S,4R)-4-fluoro-N-((5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.Step 1: Preparation of2′-chloro-5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridine

A mixture of 2-chloro-5-fluoro-4-iodopyridine (2.57 g, 9.98 mmol),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (2.00 g, 10.48 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (407.63 mg, 0.50 mmol), sodium carbonate (2.12 g,20.00 mmol) in water (10 mL) and toluene (25 mL) was stirred forovernight at 90° C. under nitrogen. The reaction mixture wasconcentrated under reduced pressure, diluted with water, extracted withdichloromethane, and separated. The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1:5) to afford the title compound (2.31 g) ascolorless oil.

Step 2: Preparation of5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridine-2′-carbonitrile

A mixture of2-chloro-5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine (1 g, 3.62mmol), Pd₂(dba)₃.CHCl₃ (187 mg, 0.18 mmol), Zn(CN)₂ (254 mg, 2.16 mmol),DPPF (200 mg, 0.36 mmol), and Zn (24 mg, 0.37 mmol) in DMA (10 mL) wasirradiated with microwave radiation for 1 h at 125° C. under nitrogen.The reaction was then quenched with water, extracted with EtOAc. Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:5) toafford the title compound (860 mg) as a yellow solid.

Step 3: Preparation of(5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methanamine

A mixture of5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile (250mg, 0.94 mmol), Raney Ni (100 mg, 1.17 mmol) in methanol (10 mL) wasstirred for 1 h at room temperature under an atmosphere of hydrogen. Thesolids were filtered off and the filtrate was concentrated under reducedpressure to afford the crude title compound (250 mg) as brown oil, whichwas used in the next step without any further purification.

Step 4: Preparation of(2S,4R)-4-fluoro-N-((5′-fluoro-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide

A mixture of[5-fluoro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(141 mg, 0.52 mmol), HATU (231 mg, 0.61 mmol), DIPEA (157 mg, 1.21mmol),(3R,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-3-carboxylicacid (110 mg, 0.38 mmol) in DMF (5 mL) was stirred overnight at 25° C.The reaction mixture was quenched with water, extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified byPrep-HPLC to afford the title compound (32.4 mg) as a white solid. 1HNMR (300 MHz, CD₃OD) δ 9.41 (s, 1H), 8.72 (d, J=9.9 Hz, 2H), 8.58 (d,J=1.2 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 8.04-7.99 (m, 2H), 7.86 (d, J=8.4Hz, 1H), 7.37-7.31 (m, 2H), 5.16 (d, J=51.9 Hz, 1H), 4.74-4.56 (m, 2H),4.33-4.27 (m, 1H), 3.86-3.67 (m, 2H), 2.54-2.52 (m, 1H), 2.30-2.12 (m,1H).

Example 141 Preparation of (2S,4R)-4-fluoro-N-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.Step 1: Preparation of5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridine-4-carbaldehyde

A mixture of 2-bromo-5-fluoropyridine-4-carbaldehyde (300 mg, 1.47mmol), [6-(trifluoromethyl)pyridin-3-yl]boronic acid (420 mg, 2.20mmol), Pd(dppf)Cl₂. CH₂Cl₂ (60 mg, 0.07 mmol), Cs₂CO₃ (1.44 g, 0.09mmol) in water (2 mL) and 1,4-Dioxane (6 mL) was stirred overnight at90° C. in an oil bath under nitrogen. The resulting mixture was quenchedwith water, extracted with CH₂Cl₂ and separated. The combined organiclayers were washed with brine, dried (Na₂SO₄) and concentrated underreduce pressure. The residue was purified by flash chromatography onsilica gel with EtOAc/petroleum ether (12:88) to afford the titlecompound (110 mg) as a light yellow solid.

Step 2: Preparation of(5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methanamine

A mixture of5-fluoro-2-[6-(trifluoromethyl)pyridin-3-yl]pyridine-4-carbaldehyde (363mg, 1.34 mmol), NH₂OH.HCl (187 mg, 2.69 mmol) in ethanol (15 mL) andwater (3 mL) was stirred for 30 min at 25° C. Then concentrated HCl(0.08 mL, 36%), Pd/C (300 mg, 10%) was added and the reaction mixturewas stirred for 50 min at 25° C. under an atmosphere of hydrogen gas.The solids were filtered off and the filtrate was concentrated underreduced pressure. The resulting mixture was diluted with H₂O, andadjusted to pH ˜7-8 with 5 N NaHCO₃, extracted with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure to afford the crude title compound (300 mg) asyellow oil, which was used in the next step without any furtherpurification.

Step 3: Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-4-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (129 mg, 0.44 mmol), HATU (169 mg, 0.44 mmol), DIPEA (143 mg, 1.11mmol),[5-fluoro-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methanamine(100 mg, 0.37 mmol) in DMF (2 mL) was stirred for overnight at 25° C.The reaction mixture was quenched with water, extracted withdichloromethane. The combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (6:4). The crude product was recrystallized frommethanol to afford the title compound (67 mg) as an off-white solid. 1HNMR (300 MHz, CD₃OD) δ 9.08 (s, 1H), 8.61 (d, J=3 Hz, 1H), 8.43 (d, J=6Hz, 1H), 8.02-7.92 (m, 4H), 7.38-7.32 (m, 2H), 5.16 (d, J=54 Hz, 1H),4.65 (s, 2H), 4.31-4.26 (m, 1H), 3.86-3.68 (m, 2H). 2.54-2.52 (m, 1H),2.32-2.06 (m, 1H).

Example 142 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: Preparation of 1-tert-Butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(2 g, 8.57 mmol), potassium carbonate (5.9 g, 42.69 mmol), THF (80 mL)and CH₃I (6.1 g, 42.98 mmol) was stirred for 12 h at room temperature.The solids were filtered off and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with EtOAc/petroleum ether (1:5) to afford the titlecompound (800 mg, 38%) as colorless oil.

Step 2: Preparation of 1-tert-butyl 2-methyl(4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate

A 1 M solution of LiHMDS (4.85 mL, 4.85 mmol) was added dropwise into amixture of 1-tert-butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (400 mg, 1.62 mmol) in THF(20 mL) with stirring at −78° C. under nitrogen. The reaction solutionwas stirred for 30 min at −78° C. To this was added CH₃I (690 mg, 4.86mmol) dropwise at −78° C. The reaction mixture stirred for 12 h at roomtemperature, quenched with water, extracted with EtOAc, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:5) toafford the title compound (360 mg, 85%) as colorless oil.

Step 3: Preparation of 4R-4-fluoro-2-methylpyrrolidine-2-carboxylic acidhydrochloride

A mixture of 1-tert-butyl 2-methyl(4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate (360 mg, 1.38 mmol)and HCl in dioxane (10 mL, lmol/L) was stirred for 2 h at roomtemperature. The mixture was concentrated to afford the crude product(315 mg) as a light yellow solid, which was used in the next stepwithout any further purification.

Step 4: Preparation of methyl(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylate

A mixture of 4R-4-fluoro-2-methylpyrrolidine-2-carboxylate hydrochloride(315 mg, 1.60 mmol), triethylamine (485 mg, 4.80 mmol), dichloromethane(20 mL) and 4-fluorobenzene-1-sulfonyl chloride (310 mg, 1.60 mmol) wasstirred for 12 h at room temperature. The reaction was diluted withdichloromethane, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel eluting with EtOAc/petroleum ether (1:4) to afford the titlecompound (380 mg) as colorless oil, which was used in the next stepwithout any further purification.

Step 5: Preparation of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid

A mixture of methyl(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylate(380 mg, 1.19 mmol), LiOH (58 mg, 2.42 mmol), methanol (8 mL), water (2mL) was stirred for 12 h at room temperature. The reaction mixture wasconcentrated, dissolved in water, extracted with ether. The aqueouslayers was acidified with 3 N HCl (pH 2-3), extracted with EtOAc, driedover anhydrous Na₂SO₄ and concentrated to afford the title compound (260mg, 72%) as yellow oil, which was used in the next step without anyfurther purification.

Step 6:(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

A mixture of(4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-2-methylpyrrolidine-2-carboxylicacid (125 mg, 0.41 mmol), DMF (4 mL), HATU (228 mg, 0.60 mmol), DIPEA(206 mg, 1.59 mmol) and[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (104 mg, 0.36 mmol) was stirred for 12 h at roomtemperature. The mixture was diluted with water, extracted with EtOAc.The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:1 to2:1).

Slower eluting isomer (72.7 mg) assigned by potency SAR as(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide:1H NMR (300 MHz, CD₃OD) δ 9.50 (s, 1H), 9.20 (s,1H), 8.83 (d, J=8.4 Hz,1H), 8.31 (s, 1H), 8.06-7.98 (m, 3H), 7.37 (t, J=17.4 Hz, 2H), 5.26 (d,J=51 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.19-4.07(m, 1H), 3.76-3.60 (m, 1H), 2.76-2.64 (m, 1H), 2.33-2.14 (m, 1H), 1.61(s, 3H).

Example 143 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example198, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine (obtainedfollowing Example 145, steps 1, 2, 3, and standard deprotonation of theHCl salt) and Example 198, steps 2 and 3 (107 mg): 1H NMR (400 MHz,DMSO-d₆) δ 9.25 (s, 1H), 9.11 (t, J=5.7 Hz, 1H), 8.40 (d, J=8.1 Hz, 2H),8.15 (s, 1H), 8.07-7.99 (m, 2H), 7.88 (d, J=8.1 Hz, 2H), 7.47 (t, J=8.6Hz, 2H), 5.21 (d, J=52.4 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.31-4.22 (m,1H), 3.78-3.59 (m, 2H), 2.48-2.38 (m, 1H), 2.23-2.05 (m, 1H).

Example 144 Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.Step 1: Preparation of2-chloro-5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridine

A mixture of 2-chloro-5-fluoro-4-iodopyridine (1.5 g, 5.83 mmol),4-(trifluoromethyl)piperidine (890 mg, 5.81 mmol), Pd₂(dba)₃.CHCl₃ (300mg, 0.29 mmol), BINAP (360 mg, 0.58 mmol), t-BuONa (1.4 g, 14.57 mmol)in Toluene (15 mL) was irradiated with microwave radiation for 1 h at125° C. under nitrogen and quenched by water (50 mL), extracted withdichloromethane, and the organic layers was combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel with ethylacetate/petroleum ether (1:5) to afford the title compound (960 mg) as ayellow solid.

Step 2: Preparation of5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)picolinonitrile

A mixture of2-chloro-5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine (400 mg,1.42 mmol), Pd₂(dba)₃.CHCl₃ (72 mg, 0.07 mmol), Zn(CN)₂ (100 mg, 0.85mmol), Dppf (80 mg, 0.14 mmol), Zn (8 mg, 0.12 mmol) in DMA (10 mL) wasirradiated with microwave radiation for 1 h at 125 ₀C under nitrogen andquenched by water (100 mL), extracted with dichloromethane, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel with ethylacetate/petroleum ether (1:5) to afford the title compound (350 mg) as ayellow solid.

Step 3: Preparation of(5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methanamine

A mixture of5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridine-2-carbonitrile(200 mg, 0.73 mmol), 10% Pd/C (50 mg), conc.HCl (0.25 mL) in methanol(10 mL) was stirred for 1 h at room temperature under an atmosphere ofhydrogen gas. The solids were filtered out and the filtrate wasconcentrated under reduced pressure to afford the crude title compoundas a brown solid, which was used in the next step without any furtherpurification.

Step 4: Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (315 mg, 1.08 mmol), HATU (410 mg, 1.08 mmol), DIEA (0.8 mL, 4.84mmol),[5-fluoro-4-[4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]methanamine(250 mg, 0.90 mmol) in DMF (4 mL) was stirred overnight at roomtemperature. The resulting mixture was purified by Prep-HPLC with thefollowing conditions (1#Waters 2767-1): Column, X Bridge C18; mobilephase, Mobile Phase A: Water/0.05% NH₄HCO₃, Mobile Phase B: ACN=30%increasing to ACN=70% within 10 min; Detector, UV 254 nm to afford thetitle compound (28.2 mg) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.09 (s, 1H), 8.03-7.99 (m, 2H), 7.39-7.34 (m, 2H), 7.18-7.16 (d, J=7.6Hz, 2H), 5.21-5.07 (d, J=52.4 Hz, 1H), 4.47 (s, 2H), 4.28-4.24 (m, 1H),4.04-4.01 (d, J=12.8 Hz, 2H), 3.83-3.70 (m, 2H), 3.00-2.94 (t, J=12.8Hz, 2H), 2.51-2.40 (m, 2H), 2.25-2.12 (m, 1H), 1.94-1.91 (d, J=12.8 Hz,2H), 1.71-1.65 (m, 2H).

Example 145 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: Preparation of 4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine

A mixture of 4,6-dichloropyrimidine (2.17 g, 14.57 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (1 g, 4.86 mmol), Pd(dppf)Cl₂(731 mg, 1.00 mmol), potassium carbonate (5 g, 36.18 mmol), dioxane (40mL) and water (4 mL) was stirred for 12 h at 100° C. under nitrogen. Themixture was diluted with EtOAc, washed with brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel eluting with EtOAc/petroleum ether (1/50) to afford the titlecompound (1.1 g, 82%) as a white solid.

Step 2: Preparation of6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile

A mixture of 4-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine (820 mg,2.99 mmol), Zn(CN)₂ (421 mg, 3.58 mmol), Pd(PPh3)4 (347 mg, 0.30 mmol),DMF (6 mL) was stirred for 9 h at 100° C. under nitrogen. The reactionwas cooled, diluted with water (30 mL), extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/50)to afford the title compound (320 mg, 40%) as a white solid.

Step 3: Preparation of(6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methanamine hydrochloride

A mixture of 6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile(160 mg, 0.60 mmol), ethanol (10 mL), concentrated HCl solution (0.02mL), 10% Palladium on carbon (100 mg) was stirred for 10 min at roomtemperature under an atmosphere of hydrogen gas. The solids werefiltered off and the filtrate was concentrated to afford the crudeproduct (200 mg) as a solid, which was used in the next step without anyfurther purification.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrro-lidine-2-carboxylicacid (150 mg, 0.51 mmol), DMF (4 mL), DIPEA (263 mg, 2.03 mmol), HATU(294 mg, 0.77 mmol) and[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanamine (200 mg, 0.74mmol) was stirred for 12 h at room temperature. The crude solution waspurified directly by Prep-HPLC to afford the title compound (51 mg, 13%)as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 9.15 (s, 1H), 8.41 (d, J=8.7Hz, 6H), 8.25 (s, 1H), 8.08-8.03 (m, 2H), 7.40-7.34 (m, 4H), 5.17 (d,J=51.6 Hz, 1H), 4.63 (d, J=4.8 Hz, 2H), 4.37-4.31 (m, 1H), 3.88-3.75 (m,2H), 2.61-2.48 (m, 1H), 2.35-2.11 (m, 1H).

Example 146 Preparation of(2S,4R)-N-([3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-pyrrolidine-2-carboxylicacid (48 mg, 0.16 mmol), DIPEA (63 mg, 0.49 mmol), DMF (3 mL), HATU (94mg, 0.25 mmol) and[3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine(46 mg, 0.17 mmol) was stirred for 2 h at room temperature. The reactionmxture was purified directly by Prep-HPLC to afford the title compound(40 mg, 44%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 9.16 (s, 1H),8.55 (s, 1H), 8.33-8.37 (m, 1H), 7.94-8.02 (m, 3H), 7.32-7.38 (m, 2H),5.15 (d, J=52.5 Hz, 1H), 4.39 (s, 2H), 4.25-4.19 (m, 1H), 3.85-3.67 (m,2H), 2.53-2.42 (m, 1H), 2.29-2.10 (m, 1H).

Example 147 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethylthio)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (102 mg, 0.35 mmol), DMF(5 mL), DIPEA (136 mg, 1.05 mmol), HATU(200 mg, 0.53 mmol) and(6-[4-[(trifluoromethyl)sulfanyl]phenyl]pyrimidin-4-yl)methanamine (100mg, 0.35 mmol) was stirred for 1 h at room temperature. The crudesolution was purified directly by Prep-HPLC high to afford the titlecompound (75.4 mg, 39%) as a white solid. ¹H NMR (300MHz, CD₃OD) δ 9.16(s, 1H), 8.39 (d, J=8.4 Hz, 2H), 8.27 (s, 1H), 8.07-8.01 (m, 2H), 7.79(d, J=8.4 Hz, 2H), 7.38-7.32 (m, 2H), 5.16 (d, J=51.9 Hz, 1H), 4.63 (d,J=4.2 Hz, 2H), 4.32 (dd, J=10.2, 7.2 Hz, 1H), 3.87-3.9 (m, 2H),2.57-2.15 (m, 2H).

Example 148 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)cyclohex-1-enyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: Preparation of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanol

NaBH₄ (76 mg, 2.01 mmol) was added portionwise to a solution of ethyl6-[4-(trifluoromethyl) cyclohex-1-en-1-yl]pyrimidine-4-carboxylate (300mg, 1.00 mmol) in methanol (10 mL) with stirring. The resulting mixturewas stirred for 2 h at 25° C., and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith EtOAc/petroleum ether (1:1) to afford the title compound (254 mg)as a white solid.

Step 2: Preparation of 2-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H- isoindole-1,3-dione

DIAD (235 mg, 1.16 mmol) was added dropwise to a solution of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanol (150mg, 0.58 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (94 mg, 0.64 mmol),PPh₃ (305 mg, 1.16 mmol) in THF (10 mL) at 0° C. with stirring. Theresulting mixture was stirred for 2 h at 25° C., then diluted withwater, extracted with dichloromethane. The organic layers were combinedand washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/petroleum ether (1:1) to afford thetitle compound (425 mg) as a white solid.

Step 3: Preparation of[6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanamine

A mixture of2-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(425 mg, 1.10 mmol), hydrazine hydrate (80%) (0.5 mL) in methanol (10mL) was stirred for 3 h at 25° C., and concentrated under reducedpressure. The residue was dissolved in EtOAc, and the solids werefiltered out. The filtrate was concentrated under reduced pressure toafford the crude title compound (210 mg) as a white solid, which wasused in the next step without any further purification.

Step 4: Preparation of (2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(4-(trifluoromethyl)cyclohex-1-enyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

A mixture of [6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methanamine (284 mg, 1.10 mmol), HATU(465.8 mg, 1.23 mmol), DIPEA (317 mg, 2.45 mmol) in DMF (5 mL) wasstirred for 10 min at 25° C. Then(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (210 mg, 0.72 mmol) was added and the resulting mixture was astirred overnight at 25° C.. The reaction mixture was then quenched withwater, extracted with dichloromethane. The combined organic layers werewashed with brine (2×10 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product (120 mg) waspurified by Prep-HPLC to afford the title compound (25.8 mg) as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 8.99 (s, 1H), 8.04 (q, J=6 Hz, 2H),7.84 (s, 1H), 7.38 (t, J=9 Hz, 2H), 7.15 (s, 1H), 5.16 (d, J=51 Hz, 1H),4.88-4.86 (d, J=6 Hz, 2H), 4.31 (t, J=9 Hz, 1H), 3.86-3.72 (m, 2H), 2.84(m, 1H), 2.59-2.47 (m, 4H), 2.32-2.14 (m, 3H), 1.67-1.61 (m, 1H).

Example 149 Preparation of((2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-((1r,4S)-4-(trifluoromethyl)cyclohexyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[4-(trifluoromethyl)cyclohex-1-en-1-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide(180 mg, 0.34 mmol), 10% Pd(OH)₂/C (30 mg) in methanol (20 mL) wasstirred for 15 min at 25° C. under an atmosphere of hydrogen gas. Thesolids were filtered off and the filtrate was concentrated under reducedpressure. The residue (260 mg) was purified by Prep-HPLC to afford amixture of cis/trans-isomers (120 mg). The isomers were separated byChiral-Prep-HPLC eluting with Hex and IPA (hold 30.0% IPA in 20 min).Faster eluting isomer (33.6 mg) arbitrarily assigned as trans isomer(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[(1r,4S)-4-(trifluoromethyl)cyclohexyl]pyrimidin-4-yl]methyl) pyrrolidine-2-carboxamide: ¹H NMR (300MHz, CD₃OD) δ 8.97 (s, 1H), 8.04 (q, J=6 Hz, 2H), 7.71 (s, 1H), 7.37 (t,J=9 Hz, 2H), 5.16 (d, J=54 Hz, 1H), 4.54 (s, 2H), 4.32 (t, J=9 Hz, 1H),3.86-3.72 (m, 2H), 2.72 (t, J=3 Hz, 1H), 2.51 (m, 1H), 2.27-2.04 (m,6H), 1.74-1.53 (m, 2H), 1.50-1.44 (m, 2H).

Slower eluting isomer (18 mg), arbitrarily assigned as cis isomer(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-[(1s,4R)-4-(trifluoromethyl)cyclohexyl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide:NMR (300 MHz, CD₃OD) δ 9.02 (s, 1H), 8.01 (q, J=6 Hz, 2H), 7.74 (s, 1H),7.36 (t, J=9 Hz, 2H), 5.15 (d, J=54 Hz, 1H), 4.56 (d, J=3 Hz, 2H), 4.27(t, J=9 Hz, 1H), 3.86-3.72 (m, 2H), 3.03-3.00 (m, 1H), 2.53-2.51 (m,1H), 2.35-2.06 (m, 5H), 1.88-1.61 (m, 6H).

Example 150 Preparation of(2S,4R)-1-(3,4-difluorophenylsulfonyl)-4-fluoro-N-((6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example198, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand (6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)methanamine, andExample 198, steps 2 and 3 using 3,4-difluorobenzene-1-sulfonyl chlorideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.29 (s, 1H), 8.33 (d, J=8.1Hz, 2H), 8.08 (s, 1H), 7.82-7.61 (m, 5H), 7.41-7.33 (m, 1H), 5.11 (d,J=51.9 Hz, 1H), 4.95-4.88 (m, 1H), 4.71-4.65 (m, 1H), 4.33 (dd, J=7.4Hz,J=9.9 Hz, 1H), 3.94-3.69 (m, 2H), 2.67-2.53 (m, 1H), 2.40-2.23 (m, 1H).

Example 151 Preparation of(2S,4R)-N-([3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.Step 1: Preparation of2-(cyclopropanecarbonyl)-3-ethoxyprop-2-enenitrile

A mixture of 3-cyclopropyl-3-oxopropanenitrile (5.5 g, 50.40 mmol),(diethoxymethoxy)ethane (74.7 g, 504.05 mmol), acetic anhydride (60 mL,634.74 mmol) was stirred for 2 h at 150° C.. The mixture was cooled,concentrated under reduced pressure. The residue was recrystallized fromethanol to afford the title compound (6 g, 72%) as a light yellow solid.

Step 2: Preparation of 3-cyclopropyl-1H-pyrazole-4-carbonitrile

A mixture of 2(cyclopropanecarbonyl)-3-ethoxyprop-2-enenitrile (2 g,12.11 mmol), hydrazine hydrate (85%) (6.1 g, 121.85 mmol) and ethanol(20 mL) was stirred for 10 min at room temperature. The mixture wasconcentrated under reduced pressure. The residue was re-crystallizedfrom toluene to afford the title compound (1 g, 62%) as a yellow solid.

Step 3: Preparation of3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbonitrile

A mixture of 3-cyclopropyl-1H-pyrazole-4-carbonitrile (1 g, 7.51 mmol),5-bromo-2-(trifluoromethyl)pyridine (2.88 g, 12.74 mmol), CuI (143 mg,0.75 mmol), L-proline (173 mg, 1.50 mmol), potassium carbonate (2.28 g,16.50 mmol) and DMSO (50 mL) was stirred for 12 h at 100° C. undernitrogen. The mixture was cooled, diluted with EtOAc, washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel elutingwith petroleum ether/EtOAc (50/1) to afford the title compound (1.1 g,53%) as a white solid.

Step 4: Preparation of[3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine

A mixture of3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbonitrile(1 g, 3.59 mmol), methanol (50 mL) and Raney Ni (500 mg, 5.84 mmol) wasstirred for 15 min at room temperature under an atmosphere of hydrogengas. The solids were filtered off, and the filtrate was concentratedunder reduced pressure to afford the title compound (900 mg) as a whitesolid, which was used in the next step without any further purification.

Step 5: Preparation of(2S,4R)-N-([3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (80 mg, 0.27 mmol), DMF (5 mL), DIPEA (106.8 mg, 0.83 mmol), HATU(156.6 mg, 0.41 mmol) and3-cyclopropyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-ylmethanamine(77.55 mg, 0.27 mmol) was stirred for 1 h at room temperature. The crudesolution was purified directly by Prep-HPLC to afford the title compound(50 mg, 33%) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.66 (s, 1H), 8.49 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.02-7.96 (m, 3H),7.74 (m, 1H), 5.27-5.10 (m, 1H), 4.33-4.30 (m, 2H), 4.19-4.14 (m, 1H),3.71-3.67 (m, 1H), 3.62-3.58 (m, 1H), 2.51 (m, 1H), 2.42-2.29 (m, 1H),2.18-1.94 (m, 1H), 0.96-0.90 (m, 4H).

Example 152 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((2-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: Preparation of4-chloro-2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine

A mixture of 4,6-dichloro-2-methylpyrimidine (1 g, 6.13 mmol),[6-(trifluoromethyl)pyridin-3-yl]boronic acid (229 mg, 1.20 mmol),potassium carbonate (2.07 g, 14.98 mmol), dioxane (50 mL), water (2 mL)and Pd(dppf)Cl₂ (320 mg, 0.44 mmol) was irradiated with microwaveradiation for 3 h at 100° C. under nitrogen. The mixture was dilutedwith EtOAc (150 mL), washed with brine (3×50 mL), dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/10)to afford the title compound (1.1 g, 66%) as a white solid.

Step 2: Preparation of2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carbonitrile

A mixture of4-chloro-2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine (300 mg,1.10 mmol), DMF (5 mL), Zn(CN)₂ (128.7 mg, 1.10 mmol), dppf (60.9 mg,0.11 mmol) and Pd2(dba)3CHCl3 (113.9 mg, 0.11 mmol) was irradiated withmicrowave radiation for 3 h at 120° C. under nitrogen. The mixture wasdiluted with EtOAc (100 mL), washed with brine (3×), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/10)to afford the title compound (250 mg, 86%) as a white solid.

Step 3: Preparation of[2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrogen chloride

A mixture of2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carbonitrile(250 mg, 0.94 mmol), ethanol (20 mL), concentrated HCl (0.2 mL) and 10%Palladium carbon (200 mg) was stirred for 5 min at room temperatureunder an atmosphere of hydrogen gas. The solids were filtered off andthe filtrate was concentrated to afford the crude product (200 mg) as ablack solid, which was used in the next step without any furtherpurification.

Step 4: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-42-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (107.7 mg, 0.37 mmol), DMF (5 mL), DIPEA (144.4 mg, 1.12 mmol),HATU (212.8 mg, 0.56 mmol) and[2-methyl-6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrogen chloride (112 mg, 0.37 mmol) was stirred for 1 h at roomtemperature. The crude solution was purified directly by Prep-HPLC toafford the title compound (32.9 mg, 16%) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.69 (d, J=7.2 Hz, 1H), 7.94-7.91 (m, 3H),7.89 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.28-7.23 (m, 1H), 5.09 (d, J=52.2Hz ,1H), 4.94-4.89 (m, 1H), 4.50-4.45 (m ,1H), 4.37-4.31 (m, 1H),3.96-3.62 (m, 2H), 2.83 (s, 3H), 2.64-2.54 (m, 1H), 2.34-1.52 (m, 1H).

Example 153 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

Step 1: Preparation of ethyl3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carboxylate

A mixture of CuI (122.93 mg, 0.65 mmol, 0.10 equiv), L-proline (148.8mg, 1.29 mmol, 0.20 equiv), potassium carbonate (1.786 g, 12.92 mmol,2.00 equiv), ethyl 3-methoxy-1H-pyrazole-4-carboxylate (1.1 g, 6.46mmol, 1.00 equiv), and 5-bromo-2-(trifluoromethyl)pyridine (2.185 g,9.67 mmol, 1.50 equiv) in DMSO (60 mL) was stirred overnight at 100° C.under nitrogen. The reaction solution was diluted with water andextracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column with ethylacetate/petroleum ether (1:6) to afford the title compound (790 mg, 39%)as a white solid.

Step 2: Preparation of[3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methano

LiAlH₄ (190.61 mg, 5.02 mmol, 1.50 equiv) was added in several batchesinto a solution of ethyl3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carboxylate(790 mg, 2.51 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 0° C. Theresulting solution was stirred for 30 min at 0° C. The reaction was thenquenched by water and the solids were filtered out. The resultingsolution was extracted with ethyl acetate and the organic layers werecombined. The organic was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:12) toafford the title compound (462 mg, 67%) as a yellow solid.

Step 3: Preparation of3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbaldehyde

A mixture of [3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanol (460 mg, 1.68mmol, 1.00 equiv) and PCC (714.43 mg, 3.31 mmol, 2.00 equiv) indichloromethane (20 mL) was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:12) to afford the title compound (283 mg, 62%) as a lightyellow solid.

Step 4: Preparation of [3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine

A mixture of3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazole-4-carbaldehyde(450 mg, 1.66 mmol, 1.00 equiv), ethanol (20 mL), water (1 mL), andhydroxylamine hydrochloride (229.15 mg, 3.30 mmol, 2.00 equiv) wasstirred for 2 h at room temperature. Then the flask was purged andmaintained with H₂ (g). Concentrated hydrogen chloride (0.1 mL) and Pd/C(300 mg, 10%) were added to the above mixture. The resulting solutionwas stirred for 15 min at room temperature. The solids were filtered outand the filtrate was concentrated under vacuum. The resulting solutionwas diluted with water. The pH value of the solution was adjusted to 8with sodium bicarbonate. The resulting solution was extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (280 mg, 62%) as a graysolid.

Step 5: Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (64.13 mg, 0.22 mmol, 1.20 equiv), HATU (104.89 mg, 0.28 mmol, 1.50equiv), DIEA (71.21 mg, 0.55 mmol, 3.00 equiv), and[3-methoxy-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine(50 mg, 0.18 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) wasstirred for 45 min at room temperature. The reaction was then quenchedby water. The solids were collected by filtration. The crude product waspurified by Prep-HPLC to afford the title compound (41.5 mg, 41%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 8.57-8.51 (m, 2H), 8.02-7.88 (m, 6H),7.47-7.41 (t, 2H), 4.42-4.36 (m, 1H), 4.15-4.05 (m, 5H), 3.57-3.51 (t,1H), 3.42-3.35 (m, 1H).

Example 154 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.Step 1: (2S,4R)-tert-butyl4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidine-1-carboxylate

(2S,4R)-tert-butyl4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidine-1-carboxylatewas prepared by the procedure described in Example 198, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid.

Step 2:(2S,4R)-4-fluoro-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)pyrrolidiniumchloride

(2S,4R)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide was prepared by the procedure described in Example 198,step 2.

Step 3:(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared by the procedure described in Example198, step 3 (29 mg): ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J=1.9 Hz, 1H),9.30 (d, J=1.2 Hz, 1H), 9.11 (t, J=5.9 Hz, 1H), 8.79 (dd, J=8.3 Hz,J=1.7 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.05-7.98 (m, 2H),7.47 (t, J=8.8 Hz, 2H), 5.21 (d, J=52.4 Hz, 1H), 4.53 (d, J=5.9 Hz, 2H),4.25 (dd, J=9.8, 7.2 Hz, 1H), 3.79-3.60 (m, 2H), 2.46-2.37 (m, 1H),2.25-2.04 (m, 1H).

Example 155 Preparation of (2S,4R)-N-((6-(4-cyclopropylphenyl)pyrimidin-4-yl)methyl)-4-fluoro-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxylicacid (155.2 mg, 0.53 mmol), HATU (253.3 mg, 0.67 mmol), DIPEA (172 mg,1.33 mmol), [6-(4-cyclopropylphenyl)pyrimidin-4-yl]methanamine (100 mg,0.44 mmol) in DMF (5 mL) was stirred overnight at 25° C.. The reactionmixture was quenched with water (20 mL), extracted with CH₂Cl₂ (3×) andseparated. The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by Prep-HPLC to afford the title compound (36.4 mg)as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 1H), 8.04 (d, J=8Hz, 3H), 7.94-7.90 (m, 2H), 7.26-7.21 (m, 2H), 7.05 (d, J=8.4 Hz, 2H),5.06 (d, J=52 Hz, 1H), 4.48 (dd, J =17.6Hz, J=8.8 Hz, 2H), 4.23-4.18 (m,1H), 3.76-3.63 (m, 2H), 2.43-2.39 (m, 1H), 2.17-2.04 (m, 1H), 1.86-1.81(m, 1H), 0.92-0.90 (m, 2H), 0.65-0.63 (m, 2H).

Example 156 Preparation of(2S,4R)-1-(3,4-difluorophenylsulfonyl)-4-fluoro-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide.

The title compound was prepared by the procedures described in Example198, step 1 using(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acidand(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine,Example 198, step 2 and Example 198, step 3 using3,4-difluorobenzene-1-sulfonyl chloride as a light yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 9.52 (s, 1H), 9.28 (s, 1H), 8.70 (d, J=7.8 Hz, 1H),8.09 (s, 1H), 7.83-7.68 (m, 3H), 7.61-7.58 (m, 1H), 7.42-7.33 (m, 1H),5.11 (d, J=51.6 Hz, 1H), 4.99-4.92 (m, 1H), 4.62-4.55 (m, 1H), 4.35 (t,J=9 Hz, 1H), 3.95-3.64 (m, 2H), 2.65-2.57 (m, 1H), 2.37-2.02 (m, 1H).

Example 157 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]-2-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 55.

1H NMR (400 MHz, DMSO) δ 9.52-9.47 (s, 2H), 9.15-9.06 (t, J=6.0 Hz, 1H),8.77-8.71 (dd, J=4.8, 1.2 Hz, 1H), 8.05-7.96 (m, 2H), 7.90-7.83 (m, 2H),7.54-7.45 (m, 2H), 5.30-5.12 (m, 1H), 4.64-4.46 (m, 2H), 4.46-4.37 (m,1H), 3.71-3.62 (ddd, J=9.8, 5.6, 2.1 Hz, 1H), 3.21-3.12 (m, 1H),2.29-2.05 (m, 2H)., LCMS (ESI) m/z:528.2 [M+H]+

Example 158 Preparation of(2S,4R)-N-[[2-chloro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.39-9.36 (s, 2H), 9.00-8.92 (t, J=5.9 Hz, 1H),8.02-7.94 (m, 3H), 7.90-7.85 (dd, J=8.3, 2.3 Hz, 1H), 7.72-7.68 (d,J=8.3 Hz, 1H), 7.49-7.40 (m, 2H), 5.29-5.09 (d, J=52.2 Hz, 1H),4.51-4.46 (d, J=5.9 Hz, 2H), 4.27-4.19 (dd, J=10.0, 7.1 Hz, 1H),3.73-3.56 (m, 2H), 2.46-2.35 (m, 1H), 2.21-2.00 (m, 1H)., LCMS (ESI)m/z:561.2 [M+H]+

Example 159 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 8.98-8.91 (t, J=6.0 Hz, 1H), 8.64-8.59 (dd,J=5.0, 0.8 Hz, 1H), 8.25-8.19 (m, 2H), 8.03-7.96 (m, 2H), 7.96-7.93 (dd,J=1.6, 0.9 Hz, 1H), 7.52-7.41 (m, 5H), 7.36-7.31 (dd, J=5.0, 1.5 Hz,1H), 5.31-5.11 (d, J=52.3 Hz, 1H), 4.55-4.37 (m, 2H), 4.25-4.16 (dd,J=9.9, 7.1 Hz, 1H), 3.76-3.57 (m, 2H), 2.47-2.35 (m, 1H), 2.21-2.00 (m,1H)., LCMS (ESI) m/z:542.2 [M+H]+

Example 160 Preparation of(2S,4R)-N-[[2-[4-(difluoromethoxy)phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 8.99-8.88 (t, J=6.0 Hz, 1H), 8.62-8.56 (dd,J=5.0, 0.7 Hz, 1H), 8.20-8.12 (m, 2H), 8.04-7.96 (m, 2H), 7.94-7.89 (dd,J=1.6, 0.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.45-7.13 (m, 1H), 7.31-7.22 (m,3H), 5.31-5.10 (m, 1H), 4.53-4.36 (m, 2H), 4.26-4.16 (dd, J=9.9, 7.1 Hz,1H), 3.78-3.58 (m, 2H), 2.47-2.35 (m, 1H), 2.20-1.98 (dddd, J=42.5,13.7, 9.9, 3.4 Hz, 1H)., LCMS (ESI) m/z:524.2 [M+H]+

Example 161 Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Following the same procedure of Example 163, step 2: The title compound(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide(39 mg, 60%) was prepared from(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide1 (62 mg, 0.12 mmol), 2-bromo-5-(trifluoromethyl)pyridine (37 mg, 0.17mmol), cesium carbonate 1 M in water (0.16 mL, 0.16 mmol), Pd(amphos)Cl₂(7 mg, 0.009 mmol) in acetonitrile (1 mL). LC/MS (ESI+): m/z 544.2(M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J=2.2 Hz, 1H), 8.89 (t, J=5.9 Hz,1H), 8.44-8.20 (m, 1H), 8.07-7.93 (m, 2H), 7.93-7.72 (m, 2H), 7.56-7.29(m, 3H), 5.12 (t, J=2.7 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 4.21 (dd,J=9.9, 7.1 Hz, 1H), 3.79-3.50 (m, 2H), 2.47-2.29 (m, 1H), 2.08 (dddd,J=42.5, 13.8, 9.9, 3.4 Hz, 1H).

Example 162: Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Following the same procedure of Example 163, step 2: The title compound(2S,4R)-4-fluoro-1-(4-fluorophenyl) sulfonyl-N4[[2-fluoro-5-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidine-2-carboxamide (15 mg, 14%) was prepared from(2S)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide1 (108 mg, 0.21 mmol), 2-chloro-5-(trifluoromethyl)pyridine (52 mg, 0.29mmol), cesium carbonate 1 M in water (0.6 mL, 0.6 mmol), Pd(amphos)Cl₂(11 mg, 0.016 mmol) in acetonitrile (1 mL). LC/MS (ESI+): m/z 544.2(M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.02 (dq, J=2.5, 1.0 Hz, 1H), 8.87 (t, J=5.8Hz, 1H), 8.28-8.11 (m, 3H), 8.01-7.92 (m, 2H), 7.48-7.41 (m, 2H), 7.38(dd, J=9.8, 8.6 Hz, 1H), 5.37-5.04 (m, 1H), 4.55-4.37 (m, 2H), 4.30-4.13(m, 1H), 3.81-3.49 (m, 2H), 2.46-2.28 (m, 1H), 2.08 (dddd, J=42.1, 13.8,9.8, 3.7 Hz, 1H).

Example 163 Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(6-(trifluoromethyl)pyridazin-3-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Step 1:(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide2

To a microwave vial was added(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide1(prepared following the same procedure of Example 177, step 1-3) (1.2g, 2.5 mmol), Pd(dppf)Cl₂ (210 mg, 0.25 mmol), bis(pinacolato)diboron(960 mg, 3.8 mmol), potassium acetate (740 mg, 7.5 mmol) and dioxane (5mL). The reaction mixture was purged with nitrogen gas for 3 minutes andthen heated to 85° C. in the microwave for 16 hours. Upon cooling toroom temperature, the resulting mixture was diluted with DCM, filteredthrough a thin layer of celite, and concentrated under reduced pressureto afford the crude product 2 (1.3, 100%).

LC/MS (ESI+): m/z 525.5 (M+H).

Step 2:(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[6-(trifluoromethyl)pyridazin-3-yl]phenyl]methyl]pyrrolidine-2-carboxamide

To a microwave vial was added(2S)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide2 (108 mg, 0.2059 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (52.63mg, 0.2883 mmol), cesium carbonate 1 M in water (0.6 mL, 0.6 mmol),acetonitrile (0.8 mL) and Pd(amphos)Cl₂ (11.67 mg, 0.016 mmol) wereadded and the reaction mixture was purged with nitrogen gas for 3minutes and then heated to 140° C. in the microwave for 30 minutes. Uponcooling to room temperature, the resulting mixture was filtered througha thin layer of celite, washed with water and extracted with ethylacetate. The combined organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase HPLC to afford the title compound (39 mg, 25%) as a white solid.

LC/MS (ESI+): m/z 545.2 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J=5.9 Hz, 1H), 8.49 (d, J=9.2 Hz,1H), 8.33 (d, J=9.0 Hz, 1H), 8.26 (ddd, J=10.6, 5.8, 2.5 Hz, 2H),8.04-7.89 (m, 2H), 7.56-7.32 (m, 3H), 5.35-5.02 (m, 1H), 4.62-4.36 (m,2H), 4.21 (dd, J=9.8, 7.2 Hz, 1H), 3.82-3.64 (m, 1H), 3.58 (dd, J=13.4,2.7 Hz, 1H), 2.39 (dt, J=17.5, 8.8 Hz, 1H), 2.08 (dddd, J=42.0, 13.8,9.7, 3.5 Hz, 1H).

Example 164 Preparation of(2S,4R)-N-(2-cyano-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamide 1 wasprepared following the same procedure of Example 176, step 1 to 5.

Following the same HATU coupling procedure of Example 176, step 6:(2S,4R)-tert-butyl2-(2-carbamoyl-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl carbamoyl)-4-fluoropyrrolidine-1-carboxylate 2 (387 mg, 75%) was preparedfrom (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylicacid (259.9 mg, 1.11 mmol) and2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamide 1 (300mg, 1.01 mmol), DIPEA (0.530 mL, 3.04 mmol), HATU (471.6 mg, 1.2 mmol)in DMF (4 mL). LC/MS (ESI+): m/z 512.5 (M+H).

Following the same procedure of Example 176, step 7:(2S,4R)-N-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide3 (180 mg, 52%) was prepared from (2S,4R)-tert-butyl2-(2-carbamoyl-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate2 (387 mg, 0.76 mmol), 4 N HCl in dioxane (1.9 mL, 7.6 mmol) followed bythe reaction with Et₃N (1.7 mL, 12.15 mmol), 4-fluorobenzenesulfonylchloride (142 mg, 0.73 mmol) in DCM (1 mL).

LC/MS (ESI+): m/z 570.5 (M+H).

Following the same procedure of Example 176, step 8: The title compound(129 mg, 78%) was prepared from(2S,4R)-N-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide3 (180 mg, 0.3 mmol), trifluoroacetic anhydride (0.08 mL, 0.6 mmol),Et₃N (0.04 mL, 0.32 mmol) in DCM (5 mL). LC/MS (ESI+): m/z 552.5 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 2H), 9.09 (t, J=5.8 Hz, 1H), 8.11-8.05 (m, 2H), 8.03 (dd, J=8.0, 1.9 Hz, 1H), 8.01-7.94 (m, 2H), 7.57-7.31(m, 2H), 5.34-5.07 (m, 1H), 4.69-4.52 (m, 2H), 4.20 (dd, J=10.0, 7.1 Hz,1H), 3.79-3.70 (m, 1H), 3.70-3.53 (m, 1H), 2.41 (td, J=16.3, 15.8, 6.7Hz, 1H), 2.24-2.00 (m, 1H).

Example 165 Preparation of(2S,4R)-N-((2-chloro-6-(4-(difluoromethoxy)phenyl)pyridin-4-yl)methyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Following the HATU coupling procedure of Example 183, step 1: tert-butyl(2S,4R)-2-[(2-bromo-6-chloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate3 (4 g, 93%) was prepared from(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid 1(2.3 g, 9.9 mmol) and (2-bromo-6-chloro-4-pyridyl)methanamine 2 (2.4 g,11 mmol), DIPEA (5.2 mL, 30 mmol), HATU (4.6 g, 12 mmol) in DMF (39 mL).LC/MS (ESI+): m/z 437.7 (M+H).

Following the same procedure of Example 183, step 2:(2S,4R)-N-[(2-bromo-6-chloro-4-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide4 (2.3 g, 100%) was prepared from tert-butyl(2S,4R)-2-[(2-bromo-6-chloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate3 (3 g, 6.9 mmol) and 4 N HCl in dioxane (8.6 mL, 34 mmol). LC/MS(ESI+): m/z 337.7 (M+H).

Following the same procedure of Example 183, step 3:(2S,4R)-N-[(2-bromo-6-chloro-4-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide5 (2.2 g, 60%) was prepared from tert-butyl(2S,4R)-2-[(2-bromo-6-chloro-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate4 (2.5 g, 7.4 mmol), Et₃N (21 mL, 0.148 mol), 4-fluorobenzenesulfonylchloride (1.7 g, 8.9 mmol) in DCM (10 mL). LC/MS (ESI+): m/z 495.7(M+H).

Following the same procedure of Example 183, step 4: The title compound(2S,4R)-N-[[2-chloro-6-[4-(difluoromethoxy)phenyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(18 mg, 28%) was prepared from(2S,4R)-N-[(2-bromo-6-chloro-4-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide5 (54 mg, 0.11 mmol), [5-(trifluoromethyl)pyrimidin-2-yl]boronic acid(30 mg, 0.16 mmol), cesium carbonate 1 M in water (0.16 mL, 0.16 mmol),Pd(dppf)Cl₂ (11 mg, 0.016 mmol) in acetonitrile (1 mL). LC/MS (ESI+):m/z 558.2 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J=2.2 Hz, 1H), 8.89 (t, J=5.9 Hz,1H), 8.44-8.20 (m, 1H), 8.07-7.93 (m, 2H), 7.93-7.72 (m, 2H), 7.56-7.29(m, 3H), 5.12 (t, J=2.7 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 4.21 (dd,J=9.9, 7.1 Hz, 1H), 3.79-3.50 (m, 2H), 2.47-2.29 (m, 1H), 2.08 (dddd,J=42.5, 13.8, 9.9, 3.4 Hz, 1H).

Example 166 Preparation of(2R,3S)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of4-([[(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate

A solution of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(318 mg, 1.38 mmol, 1.00 equiv), DIEA (356 mg, 2.75 mmol, 2.00 equiv),HATU (525 mg, 1.38 mmol, 1.00 equiv), and methyl4-(aminomethyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate(430 mg, 1.38 mmol, 1.00 equiv) in DMF (10 mL) was stirred for 1 h at20° C. The resulting solution was diluted with ethyl acetate, washedwith water, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withDCM/MeOH (10:1) to afford the title compound (450 mg, 62%) as a whitesolid.

Step 2: Preparation of4-([[(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylic acid

A solution of methyl4-([[(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylate(280 mg, 0.53 mmol, 1.00 equiv) and LiOH (64 mg, 2.67 mmol, 5.00 equiv)in THF (2 mL)/water (2 mL) was stirred for 4 h at room temperature. Theresulting solution was diluted with water. The pH value of the solutionwas adjusted to 4 with AcOH, extracted with ethyl acetate, washed withwater and brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in 180 mg (66%) of the title compound as ayellow solid.

Step 3: Preparation of tert-butyl(2S,3R)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate

A solution of4-([[(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidin-2-yl]formamido]methyl)-6-[6-(trifluoromethyl)pyridin-3-yl]pyridine-3-carboxylicacid (180 mg, 0.35 mmol, 1.00 equiv), HATU (147 mg, 0.39 mmol, 1.10equiv), DIEA (182 mg, 1.41 mmol, 4.00 equiv), and NH₄Cl (20.58 mg, 0.38mmol, 1.10 equiv) in DMF (5 mL) was stirred for 3 h at room temperature.The reaction was quenched with water, extracted with ethyl acetate,dried over anhydrous sodium sulfate, and concentrated under vacuum. Thisresulted in 155 mg (86%) of the title compound as brown oil.

Step 4: Preparation of tert-butyl(2R,3S)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate

DAST (237.2 mg, 1.47 mmol, 5.00 equiv) was added to the solution oftert-butyl(2S,3R)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-hydroxypyrrolidine-1-carboxylate (150 mg, 0.29 mmol, 1.00equiv) in chloroform (2 mL) dropwise at 0° C. The resulting solution wasstirred for 2 h at room temperature and then quenched with of water,extracted with dichloromethane, washed with sodium bicarbonate/water,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (3/2) to afford the title compound (50 mg, 33%)as a yellow solid.

Step 5: Preparation of tert-butyl(2R,3S)-2-[([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate

A solution of tert-butyl(2R,3S)-2-[([5-carbamoyl-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate(40 mg, 0.08 mmol, 1.00 equiv), TFAA (32.8 mg, 0.16 mmol, 2.00 equiv),and TEA (12 mg, 0.12 mmol, 1.50 equiv) in dichloromethane (3 mL) wasstirred for 15 min at room temperature. The reaction was then quenchedwith water, extracted with dichloromethane, washed with saturated sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in 50 mg (crude) of the titlecompound as orange oil.

Step 6: Preparation of(2R,3S)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-3-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2R,3S)-2-[([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)carbamoyl]-3-fluoropyrrolidine-1-carboxylate(50 mg, 0.10 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (3 mL) was stirred for 0.5 h at room temperature. The solidswere collected by filtration. This resulted in 40 mg (92%) of the titlecompound as a dark red solid.

Step 7: Preparation of (2R,35)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

4-Fluorobenzene-1-sulfonyl chloride (19.9 mg, 102.20 mmol, 1.10 equiv)was added into a solution of(2R,3S)-N-([5-cyano-2-[6-(trifluoromethyl)pyridin-3-yl]pyridin-4-yl]methyl)-3-fluoropyrrolidine-2-carboxamidehydrochloride (40 mg, 93.06 mmol, 1.00 equiv), and TEA (28 mg, 276.70mmol, 3.00 equiv) in dichloromethane (5 mL). This was stirred for 2 h atroom temperature. The reaction was then quenched with water, extractedwith dichloromethane, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (3:2) to afford thetitle compound 12.6 mg (crude) of as a pink solid.

¹H NMR (300 MHz, CDCl₃) δ 9.48 (s, 1H), 8.95 (s, 1H), 8.68-8.65 (d,J=8.1 Hz, J=1.2 Hz, 1H), 8.11 (s, 1H), 7.93-7.89 (m, 2H), 7.82-7.79 (d,J=8.1 Hz, 1H), 7.70 (t, J=6.0 Hz, 1H), 7.32-7.26 (m, 2H), 5.39-5.22 (dd,J=49.8 Hz, J=1.8 Hz, 1H), 5.11-5.02 (dd, J=17.4 Hz, J=7.8 Hz, 1H), 4.61(dd, J=17.7 Hz, J=4.8 Hz, 1H), 4.41-4.33 (d, J=23.1 Hz, 1H), 3.83 (t,J=8.4 Hz, 1H), 3.34-3.25 (m, 1H), 2.23-1.98 (m, 2H).

Example 167 Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of[5-fluoro-2-([[(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidin-2-yl]formamido]methyl)pyridin-4-yl]boronicacid

A mixture of(2S,4R)-N-[(4-bromo-5-fluoropyridin-2-yl)methyl]-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(300 mg, 0.63 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(238 mg, 0.94 mmol, 1.50 equiv), KOAc (184 mg, 1.87 mmol, 3.00 equiv),and Pd(dppf)Cl₂ (46 mg, 0.06 mmol, 0.10 equiv) in 1,4-dioxane (20 mL)was stirred for 12 h at 75° C. under nitrogen. The solids were filteredout. The filtrate was diluted with water and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (500 mg, crude) as brown oil.

Step 2: Preparation of(2S,4R)-4-fluoro-N-((5-fluoro-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1-(4-fluorophenylsulfonyl)pyrrolidine-2-carboxamide

A mixture of[5-fluoro-2-([[(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidin-2-yl]formamido]methyl)pyridin-4-yl]boronicacid (278 mg, 0.627 mmol, 1.00 equiv),5-bromo-2-(trifluoromethyl)pyrimidine (284 mg, 1.251 mmol, 2.00 equiv),potassium carbonate (260 mg, 1.881 mmol, 3.00 equiv), and Pd(dppf)Cl₂(46 mg, 0.063 mmol, 0.100 equiv) in 1,4-dioxane (20 mL)/water (2 mL) wasstirred for 4 h at 70° C. under nitrogen. The mixture was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1/1). The crude product (100 mg) waspurified by Prep-HPLC to afford the titled compound (35.5 mg, 10%) as awhite solid.

¹H NMR (300 MHz, CDCl₃) δ 9.23 (s, 2H), 8.61 (s, 1H), 7.90-7.86 (m, 2H),7.72-7.70 (d, J=6 Hz, 1H), 7.58-7.54 (t, J=5.86 Hz, 1H), 7.26-7.24 (d,J=7.2 Hz, 2H), 5.15-4.92 (m, 2H), 4.56-4.48 (m, 1H), 4.32-4.26 (t, J=8.7Hz, 1H), 3.94-3.59 (m, 2H), 2.60-2.54 (m, 1H), 2.32-2.01 (m, 1H).

Example 168 Preparation of(2R,3S)-3-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 55.

1H NMR (400 MHz, DMSO) δ 9.69-9.65 (s, 2H), 9.16-9.09 (t, J=6.0 Hz, 1H),8.77-8.73 (m, 1H), 8.17-8.12 (s, 1H), 8.06-7.98 (m, 2H), 7.55-7.45 (m,3H), 5.30-5.13 (m, 1H), 4.59-4.42 (m, 2H), 4.42-4.33 (d, J=24.3 Hz, 1H),3.75-3.64 (ddd, J=9.4, 7.5, 2.3 Hz, 1H), 3.24-3.12 (ddd, J=10.8, 9.1,7.3 Hz, 1H), 2.25-2.05 (m, 2H)., LCMS (ESI) m/z:527.2 [M+H]+

Example 169 Preparation of(2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine

A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (10.0 g, 44.056 mmol,1.0 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(11.19 g, 44.066 mmol, 1.0 equiv), and Pd(OAc)₂ (100 mg, 0.445 mmol) inDMF (100 mL) was stirred for 12 h at 70° C. under nitrogen. The reactionmixture was then quenched with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in the title compound (10 g, 83%) as blackoil.

Step 2: Preparation of methyl5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-4-carboxylate

A mixture of5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (3g, 10.95 mmol, 1.00 equiv), methyl 2,5-dichloropyridine-4-carboxylate (6g, 29.12 mmol, 1.00 equiv), Pd(dppf)Cl₂ (1.55 g, 2.12 mmol, 0.20 equiv),and potassium carbonate (8.78 g, 63.53 mmol, 5.80 equiv) in dioxane (100mL)/water(5 mL) was stirred for 12 h at 60° C. under nitrogen. Thereaction mixture was concentrated under vacuum. The residue purified bya silica gel column eluting with ethyl acetate/petroleum ether (1:10) toafford the title compound (1.4 g, 40%) as a white solid.

Step 3: Preparation of methyl5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-4-carboxylate

A mixture of methyl5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-4-carboxylate(600.00 mg, 1.89 mmol, 1.00 equiv), Pd(dppf)Cl₂ (230.35 mg, 0.315 mmol,0.200 equiv), and Zn(CH₃)₂ (4.8 ml, 3.000 equiv, 1.2 mol/L in toluene)in dioxane (20 mL) was stirred for 12 h at 65° C. under nitrogen. Thereaction mixture was concentrated under vacuum. The residue was purifiedby a silica gel column eluting with ethyl acetate/petroleum ether (1:10)to afford the title compound (400 mg, 71%) as a white solid.

Step 4: Preparation of[5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanol

DIBAl-H (4 mL, 1 mol/L in hexanes, 3.000 equiv) was added dropwise intoa solution of methyl5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-4-carboxylate(380.00 mg, 1.278 mmol, 1.000 equiv) in THF (20 mL) at −78° C. undernitrogen. The resulting solution was stirred for 30 min at −78° C. Theresulting solution was stirred for 12 h at room temperature and quenchedby methanol. The pH value of the solution was adjusted to 9 with sodiumhydroxide (1 mol/L). The resulting solution was extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). This resultedin the title compound (250 mg, 73%) as a white solid.

Step 5: Preparation of2-([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (300.43 mg, 1.486 mmol, 2.0 equiv) was added dropwise into asolution of[5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanol(200.0 mg, 0.743 mmol, 1.0 equiv), PPh₃ (389.69 mg, 1.486 mmol, 2.0equiv), and 2,3-dihydro-1H-isoindole-1,3-dione (131.16 mg, 0.891 mmol,1.2 equiv) in THF (20 mL) at 0° C. under nitrogen. The resultingsolution was stirred for 10 min at 0° C. and 12 h at room temperature.The mixture was concentrated under vacuum. The solid was washed withethyl acetate to afford the title compound (400 mg) as a white solid.

Step 6: Preparation of[5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine

A mixture of2-([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(400.00 mg, 1.004 mmol, 1.000 equiv) and NH₂NH₂.H₂O (502.69 mg, 10.042mmol, 10.000 equiv) in methanol (40 mL) was stirred for 12 h at 60° C.The reaction mixture was concentrated under vacuum. The resultingsolution was diluted with ethyl acetate and the solids were filteredout. The liquid was concentrated under vacuum to afford the titlecompound (200 mg, 74%) as a white solid.

Step 7: Preparation of tert-butyl(2S,4R)-4-fluoro-2-[([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(130.43 mg, 0.559 mmol, 1.000 equiv), HATU (318.95 mg, 0.839 mmol, 1.500equiv), DIEA (216.83 mg, 1.678 mmol, 3.000 equiv), and[5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine(150.0 mg, 0.559 mmol, 1.0 equiv) in DMF (5 mL) was stirred for 2 h atroom temperature. The reaction mixture was diluted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1:1) to afford the title compound(200 mg, 74%) as a white solid.

Step 8: Preparation of(2S,4R)-4-fluoro-N-((5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-4-fluoro-2-[([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(200 mg, 0.414 mmol, 1.000 equiv) and saturated HCl in dioxane (20 mL)was stirred for 2 h at room temperature. The reaction mixture wasconcentrated under vacuum. This resulted in the title compound (150 mg,95%) as a white solid.

Step 9: Preparation of (2S,4R)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-N-((5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamidehydrochloride (200.00 mg, 0.522 mmol, 1.0 equiv), triethylamine (158.38mg, 1.565 mmol, 3.0 equiv), and 4-fluorobenzene-1-sulfonyl chloride(203.07 mg, 1.04 mmol, 2.0 equiv) in DCM (10 mL) was stirred for 12 h atroom temperature. The reaction was then quenched by water, extractedwith dichloromethane, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). The crudeproduct (200 mg) was re-purified by Flash-Prep-HPLC to afford the titlecompound (105.5 mg, 37%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.65 (s, 2H), 8.51 (s, 1H), 8.04 (s, 1H),7.92-7.88 (m, 2H), 7.46-7.43 (m, 1H), 7.28-7.23 (m, 2H), 5.05 (d, J=51.2Hz, 1H), 4.89-4.83 (m, 2H), 4.36-4.32 (m, 2H), 3.95-3.86 (m, 1H),3.74-3.60 (m, 1H), 2.63-2.61 (m, 1H), 2.39 (s, 3H), 2.28-2.00 (m, 1H).

Example 170 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6′-(2-methoxyethoxy)-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2,6-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine

A mixture of Pd(dppf)Cl₂ (534 mg, 0.73 mmol, 0.10 equiv), potassiumcarbonate (2 g, 14.47 mmol, 2.00 equiv), 2,6-dichloro-4-iodopyridine (2g, 7.30 mmol, 1.00 equiv), and [6-(trifluoromethyl)pyridin-3-yl]boronicacid (1.39 g, 7.28 mmol, 1.00 equiv) in1,4-dioxane (80 mL)/water(8 mL)was stirred for 12 h at 60° C. under nitrogen. The solids were filteredout. The filtrate was diluted with water and extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/50) to afford the title compound (1.9 g, 89%) as a solid.

Step 2: Preparation of2-chloro-6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine

A solution of 2,6-dichloro-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine(900 mg, 3.07 mmol, 1.00 equiv) and 1-methoxy-2-(sodiooxy)ethane (1.7mL, 2.7 mmol/mL in 2-methoxyethan-1-ol, 1.50 equiv) in2-methoxyethan-1-ol (18 mL) was stirred for 12 h at 60° C. The mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (948mg, 93%) as a white solid which was used for the next step without anyfurther purification.

Step 3: Preparation of6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile

A mixture of2-chloro-6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine(400 mg, 1.202 mmol, 1.00 equiv), dppf (133 mg, 0.241 mmol, 0.20 equiv),Zn(CN)₂ (282 mg, 2.401 mmol, 2.0 equiv), and Pd₂(dba)₃CHCl₃ (62 mg,0.060 mmol, 0.050 equiv) in N,N-dimethylformamide (8 mL) was irradiatedwith microwave radiation for 1 h at 100° C. under nitrogen. The mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/5) to afford thetitle compound (350 mg, 90%) as a solid.

Step 4: Preparation of[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanaminehydrochloride

A mixture of6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridine-2-carbonitrile(1 g, 3.093 mmol, 1.00 equiv), concentrated hydrogen chloride (4 mL),and palladium on carbon (2 g) in methanol (200 mL) was stirred for 7 minat room temperature under hydrogen. The solids were filtered out. Thefiltrate was concentrated under vacuum to afford the title compound(1.43 g, crude) as a yellow solid.

Step 5: Preparation of tert-butyl(2R,4S)-4-fluoro-2-([[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl]carbamoyl)pyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(235 mg, 1.008 mmol, 1.00 equiv), DIEA (355 mg, 2.747 mmol, 2.73 equiv),HATU (418 mg, 1.099 mmol, 1.09 equiv), and6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine(300 mg, 0.917 mmol, 0.91 equiv) in N,N-dimethylformamide (8 mL) wasstirred for 10 min at room temperature. The mixture was diluted withwater and extracted with ethyl acetate. The combined extracts werewashed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (1/1) to afford the title compound(450 mg, 82%) as a white solid.

Step 6: Preparation of4-fluoro-N-[[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl]-1H-pyrrole-2-carboxamide

A solution of tert-butyl4-fluoro-2-([[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl]carbamoyl)-1H-pyrrole-1-carboxylate(450 mg, 0.836 mmol, 1.000 equiv) and trifluoroacetic acid (4 mL)indichloromethane (20 mL) was stirred for 1 h at 25° C. The resultingmixture was concentrated under vacuum. The residue was dissolved inwater. The pH value of the mixture was adjusted to 8 with saturatedsolution of sodium bicarbonate. The resulting mixture was extracted withethyl acetate. The combned extracts were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted inthe title compound (270 mg, 75%) as light yellow oil.

Step 7: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((6′-(2-methoxyethoxy)-6-(trifluoromethyl)-3,4′-bipyridin-2′-yl)methyl)pyrrolidine-2-carboxamide

A mixture of4-fluoro-N-[[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl]-1H-pyrrole-2-carboxamide(270 mg, 0.616 mmol, 1.000 equiv), triethylamine (178 mg), and4-fluorobenzene-1-sulfonyl chloride (138 mg, 0.709 mmol, 0.703 equiv) indichloromethane (30 mL) was stirred for 12 h at 25° C. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/1). The crudeproduct (300 mg) was purified by Prep-HPLC to afford the title compound(99 mg) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.97 (s, 1H), 8.13-8.10 (m, 1H), 7.93-7.87 (m,3H), 7.79-7.77 (m, 1H), 7.27-7.19 (m, 3H), 6.98 (s, 1H), 5.11- 4.98 (d,J=52 Hz, 1H), 4.98-4.63 (m, 3H), 4.53-4.48 (m, 1H), 4.35-4.30 (m, 1H),3.96-3.87 (m, 1H), 3.82-3.80 (m, 2H), 3.71-3.58 (m, 1H), 3.47 (s, 3H),2.67-2.20 (m, 2H).

Example 171 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]-3-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.45-9.37 (d, J=2.3 Hz, 2H), 9.06-8.95 (dq,J=6.2, 2.8 Hz, 1H), 8.76-8.67 (t, J=2.5 Hz, 1H), 8.47-8.38 (dt, J=9.1,2.6 Hz, 1H), 8.03-7.93 (ddd, J=8.2, 5.1, 2.4 Hz, 2H), 7.51-7.41 (td,J=8.9, 2.5 Hz, 2H), 5.30-5.07 (m, 1H), 4.52-4.38 (m, 2H), 4.24-4.13(ddd, J=9.7, 7.2, 2.4 Hz, 1H), 3.76-3.55 (m, 2H), 2.46-2.30 (td, J=16.8,16.3, 7.2 Hz, 1H), 2.20-1.98 (m, 1H)., LCMS (ESI) m/z:546.2 [M+H]+

Example 172 Preparation of(1R,4S,5S)-3-(4-fluorophenyl)sulfonyl-N-[[2-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]-3-azabicyclo[3.1.0]hexane-4- carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.68-9.63 (s, 2H), 8.92-8.85 (t, J=6.0 Hz, 1H),8.77-8.71 (d, J=5.0 Hz, 1H), 8.17-8.10 (s, 1H), 7.97-7.89 (m, 2H),7.51-7.42 (m, 3H), 4.58-4.38 (qd, J=16.7, 6.0 Hz, 2H), 4.24-4.21 (s,1H), 3.82-3.71 (dd, J=10.4, 3.4 Hz, 1H), 3.54-3.45 (d, J=10.5 Hz, 1H),1.68-1.51 (dtd, J=7.5, 5.9, 5.2, 3.7 Hz, 2H), 0.59-0.48 (td, J=7.8, 5.3Hz, 1H), -0.77- -0.89 (q, J=4.4 Hz, 1H)., LCMS (ESI) m/z:522.2 [M+H]+

Example 173 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)thiazol-4-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 8.96-8.90 (t, J=6.1 Hz, 1H), 8.65-8.59 (q,J=0.9 Hz, 1H), 8.02-7.94 (m, 2H), 7.83-7.78 (t, J=1.5 Hz, 1H), 7.72-7.66(ddd, J=9.4, 2.5, 1.6 Hz, 1H), 7.50-7.42 (m, 2H), 7.40-7.34 (ddd, J=9.7,2.4, 1.4 Hz, 1H), 5.29-5.09 (m, 1H), 4.54-4.38 (m, 2H), 4.23-4.13 (dd,J=9.9, 7.1 Hz, 1H), 3.75-3.57 (m, 2H), 2.47-2.31 (m, 1H), 2.20-1.97 (m,1H)., LCMS (ESI) m/z:550.2 [M+H]+

Example 174 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)thiazol-5-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 8.96-8.89 (t, J=6.0 Hz, 1H), 8.61-8.58 (q,J=1.1 Hz, 1H), 8.03-7.95 (m, 2H), 7.69-7.62 (m, 1H), 7.62-7.58 (t, J=1.5Hz, 1H), 7.51-7.43 (m, 2H), 7.32-7.25 (ddd, J=9.7, 2.4, 1.4 Hz, 1H),5.29-5.10 (dd, J=50.1, 3.0 Hz, 1H), 4.54-4.34 (m, 2H), 4.23-4.14 (dd,J=10.0, 7.1 Hz, 1H), 3.76-3.57 (m, 2H), 2.47-2.34 (m, 1H), 2.19-1.98 (m,1H)., LCMS (ESI) m/z:550.2 [M+H]+

Example 175 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 91.

1H NMR (400 MHz, DMSO) δ 8.92-8.86 (t, J=6.0 Hz, 1H), 8.65-8.62 (s, 1H),8.01-7.94 (m, 2H), 7.82-7.79 (t, J=1.5 Hz, 1H), 7.74-7.68 (ddd, J=9.9,2.5, 1.5 Hz, 1H), 7.49-7.41 (m, 2H), 7.26-7.20 (ddd, J=9.7, 2.4, 1.4 Hz,1H), 5.28-5.10 (d, J=52.6 Hz, 1H), 4.50-4.37 (m, 2H), 4.22-4.15 (dd,J=9.8, 7.1 Hz, 1H), 3.74-3.56 (m, 2H), 2.46-2.33 (m, 1H), 2.20-1.98 (m,1H)., LCMS (ESI) m/z:550.2 [M+H]+

Example 176 Preparation of(1S,2S,5R)-N-(2-cyano-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-3-((4-fluorophenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide.

Step 1: tert-butyl 5-bromo-1-oxo-isoindoline-2-carboxylate 2A mixture of5-bromoisoindolin-1-one 1 (5 g, 23.6 mmol), THF (50 mL),4-dimethylaminopyridine (288 mg, 2.36 mmol) and di-tert-butyldicarbonate (8 g, 35.4 mmol) was stirred for overnight at roomtemperature. The resulting mixture was concentrated under reducedpressure, diluted with ethyl acetate, washed with 10% citric acid. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel, eluting with ethyl acetate/heptane (1:1) to afford thecompound 2 (7.1 g, 96%) as a white solid. LC/MS (ESI+): m/z 313.2 (M+H).Step 2: tert-butyl1-oxo-5-[2-(trifluoromethyl)pyrimidin-5-yl]isoindoline-2-carboxylate 3

To a microwave vial was added tert-butyl5-bromo-1-oxo-isoindoline-2-carboxylate 2 (800 mg, 2.6 mmol),[5-(trifluoromethyl)pyrimidin-2-yl]boronic acid (584 mg, 3.1 mmol),potassium carbonate (1.1 g, 7.7 mmol), water (0.5 mL, 30 mmol) andPd(dppf)Cl₂ (214 mg, 0.26 mmol) in dioxane (5 mL). The reaction mixturewas purged with nitrogen gas for 3 minutes and then heated to 120° C. inthe microwave for 30 minutes. Upon cooling to room temperature, theresulting mixture was filtered through a thin layer of celite, washedwith water and extracted with ethyl acetate. The combined organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel, eluting with ethylacetate /heptane (1:1) to afford the title compound 3 (700 mg, 72%) as awhite solid. LC/MS (ESI+): m/z 380.3 (M+H).

Step 3:2-[(tert-butoxycarbonylamino)methyl]-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoicacid 4

tert-butyl1-oxo-5-[2-(trifluoromethyl)pyrimidin-5-yl]isoindoline-2-carboxylate 3(200 mg, 0.53 mmol), lithium hydroxide 1 M in water (1 mL) and THF (1mL) was stirred for 12 h at room temperature. The resulting solution wasconcentrated under reduced pressure, acidified by 10% aqueous citricacid to pH=5 and extracted with ethyl acetate twice. The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford the crude product 4 which was used withoutfurther purification. LC/MS (ESI+): m/z 398.4 (M+H).

Step 4: tert-butylN-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-1]phenyl]methyl]carbamate

2-[(tert-butoxycarbonylamino)methyl]-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoicacid 4 (300 mg, 0.75 mmol) in THF (10 mL) was treated with HATU (351 mg,0.91 mmol), DIPEA (1.5 mL, 8.3 mmol) followed by NH₄Cl (485 mg, 9.1mmol). The resulting solution was washed with saturated sodiumbicarbonate and extracted with ethyl acetate twice. The combined organiclayer was dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography on silica gel, eluting with ethylacetate/heptane (1:1) to afford the compound 5 (250 mg, 84%) as a whitesolid. LC/MS (ESI+): m/z 397.4 (M+H).

Step 5: 2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamide 6

tert-butylN-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]carbamate5 (400 mg, 1 mmol) was treated with 4N HCl in dioxane (1.8 mL, 7.4mmol), and stirred at room temperature for 30 minutes. The reaction wasconcentrated to dry and the crude product 6 was used in the next stepwithout further purification. LC/MS (ESI+): m/z 297.4 (M+H).

Step 6: tert-butyl(1R,4S,5S)-4-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-1]phenyl]methylcarbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate7

To a solution of(1R,4S,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-4-carboxylicacid (278 mg, 1.23 mmol) and2-(aminomethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]benzamide 6 (330mg, 1.11 mmol) in DMF (1 mL) was added DIPEA (0.58 mL, 3.3 mmol) andHATU (518.6 mg, 1.34 mmol). The reaction mixture was stirred for 1 h atroom temperature. The resulting mixture was diluted with ethyl acetate,washed with water, brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column, eluting with ethyl acetate/Heptane(1:1) to afford the compound 7 (499 mg, 88%) as a white solid. LC/MS(ESI+): m/z 506.5 (M+H).

Step 7:(1R,4S,5S)-N-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-azabicyclo[3.1.0]hexane-4-carboxamide8

tert-butyl(1R,4S,5S)-4-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methylcarbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate7 (387 mg, 0.7656 mmol) was treated with 4N HCl in dioxane (1.9 mL, 7.6mmol), and stirred at room temperature for 30 minutes. The reaction wasconcentrated to dry and the crude product (310 mg, 0.76 mmol) wastreated with Et₃N (2 mL, 1.415.369 mmol) in DCM (1 mL), followed by4-fluorobenzenesulfonyl chloride (179 mg, 0.92 mmol). The reaction wasstirred for overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel, eluting with ethyl acetate/heptane (1:1)to afford the compound 8 (180 mg, 40%) as yellow solid. LC/MS (ESI+):m/z 564.5 (M+H).

Step 8:(1R,4S,5S)-N-[[2-cyano-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-(4-fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-4-carboxamide

(1R,4S,5S)-N-[[2-carbamoyl-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-(4-fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-4-carboxamide8 (180 mg, 0.32 mmol) was treated with trifluoroacetic anhydride (0.09mL, 0.64 mmol) and triethylamine (0.04 mL, 0.32 mmol) in DCM (5 mL). Thereaction mixture was stirred for overnight at room temperature. Theresulting solution was concentrated and purified with reverse phase HPLCto afford the title compound (54 mg, 31%). LC/MS (ESI+): m/z 546.2(M+H).

¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 2H), 8.95 (t, J=5.8 Hz, 1H), 8.09(d, J=8.1 Hz, 1H), 8.06-7.95 (m, 2H), 7.95-7.79 (m, 2H), 7.59-7.38 (m,2H), 4.65 (dd, J=16.0, 6.1 Hz, 1H), 4.52 (dd, J=16.0, 5.5 Hz, 1H), 4.22(s, 1H), 3.74 (dd, J=10.4, 3.7 Hz, 1H), 3.47 (d, J=10.4 Hz, 1H), 1.59(tdd, J=9.6, 7.0, 3.8 Hz, 2H), 0.54 (td, J=7.8, 5.3 Hz, 1H), -0.84 (q,J=4.4 Hz, 1H).

Example 177 Preparation of(2S,4R)-4-fluoro-N-((4-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide.

Following the HATU coupling procedure of Example 35, step 1: tert-butyl(2S,4R)-2-[(5-bromo-2-fluoro-phenyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate3 (801 mg, 89%) was prepared from(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid 1(500 mg, 2.14 mmol) and (5-bromo-2-fluorophenyl)methanamine 2 (567 mg,2.55 mmol), DIPEA (1.12 mL, 6.4 mmol), HATU (998 mg, 2.57 mmol), DMF (8mL). LC/MS (ESI+): m/z 420.3 (M+H).

Following the same procedure of Example 35, step 3:(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide4 (609 mg, 100%) was prepared from tert-butyl(2S,4R)-2-[(5-bromo-2-fluoro-phenyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate3 (801 mg, 1.9 mmol) and 4 N HCl in dioxane (3.8 mL, 15.2 mmol). LC/MS(ESI+): m/z 320.3 (M+H).

Following the same procedure of Example 35, step 4:(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide6 (710 mg, 70%) was prepared from(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide4 (680 mg, 2.1 mmol), Et₃N (6 mL, 42.6 mmol), 4-fluorobenzenesulfonylchloride (710 mg, 1.5 mmol) in DCM (1 mL). LC/MS (ESI+): m/z 478.3(M+H).

Following the same procedure of Example 183, step 4: The title compound(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[4-(trifluoromethyl)phenyl]phenyl]methyl]pyrrolidine-2-carboxamide(48 mg, 39%) was prepared from(2S,4R)-N-[(5-bromo-2-fluoro-phenyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide6 (110 mg, 0.23 mmol), [4-(trifluoromethyl)phenyl]boronic acid (48 mg,0.25 mmol), cesium carbonate 1 M in water (0.32 mL, 0.32 mmol),Pd(dppf)Cl₂ (19 mg, 0.023 mmol) in acetonitrile (1 mL). LC/MS (ESI+):m/z 543.2 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 8.86 (t, J=5.8 Hz, 1H), 8.07-7.93 (m, 2H),7.89 (d, J=7.9 Hz, 2H), 7.82 (dd, J=7.2, 2.5 Hz, 1H), 7.75 (d, J=8.3 Hz,2H), 7.72-7.64 (m, 1H), 7.53-7.40 (m, 2H), 7.34 (dd, J=9.9, 8.5 Hz, 1H),5.38-4.97 (m, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.22 (dd, J=9.8, 7.1 Hz, 1H),3.79-3.65 (m, 1H), 3.65 (s, 1H), 2.43-2.29 (m, 1H).

Example 178 Preparation of(2S,4R)-N-[[2-[2-amino-6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide.Step 1: (2S,4R)-tert-butyl2-(((2-bromopyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate

The title compound (4812 mg, 98%) was prepared following the amidecoupling procedure of Example 35, Step 1 from(2-bromo-4-pyridyl)methanamine (2020 mg, 10.800 mmol),(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(2771 mg, 11.88 mmol), HATU (4610 mg, 11.88 mmol) and triethylamine(3.31 mL, 23.7 mmol) in N,N-dimethylformamide (25 mL). LC/MS (ESI+): m/z402 (M+H).

Step 2:(2S,4R)-N-((2-bromopyridin-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamide

Trifluoroacetic acid (8 ml) was added dropwise to a solution oftert-butyl(2S,4R)-2-[(2-bromo-4-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(1010 mg, 2.51 mmol) in DCM (12 ml) mixture. The mixture was stirred for2 hours, concentrated in vacuum, the residue diluted with sat aq NaHCO₃and extracted with ethyl acetate. The organic extracts were washed withbrine, dried over Na₂SO₄ and concentrated to afford 422 mg (56%). Theresidue was used without further purification. LC/MS (ESI+): m/z 302(M+H).

Step 3:(2S,4R)-N-((2-bromopyridin-4-yl)methyl)-4-fluoro-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide

The title compound (369 mg, 57%) was prepared following the sulfonamidecoupling procedure of Example 35, Step 4 from(2S,4R)-N-[(2-bromo-4-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(422 mg, 1.40 mmol), 4-fluorobenzenesulfonyl chloride (300 mg, 1.54mmol) and triethylamine (0.30 mL, 2.2 mmol) in 9 ml of DMF/DCM mixture(2:1). LC/MS (ESI+): m/z 460 (M+H).

Step 4:((2S,4R)-4-fluoro-N-((2′-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)methyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide

The title compound (174 mg, 40%) was prepared following the Suzukicoupling procedure of Example 42, Step 1 from(2S,4R)-N-[(2-bromo-4-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(369 mg, 0.80 mmol), [2-fluoro-6-(trifluoromethyl)-3-pyridyl]boronicacid (402 mg, 1.92 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (112 mg,0.15 mmol) and aqueous Cs2CO3 (1.6 mL, 1.60 mmol, 1.0 mol/L) inacetonitrile (10 mL). LCMS (ESI_Formic_MeCN): [MH⁺]=545.

Step 5:(2S,4R)-N-[[2-[2-amino-6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide

A mixture of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-fluoro-6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide(80 mg, 0.13 mmol) in DMSO (2 ml) was saturated with ammonia (gas) andthen heated at 80° C. in a sealed vial for 24 hours. The mixture wasdegassed in vacuum and submitted for RP HPLC purification to afford 51mg (71%) of the title product.

1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J=6.0 Hz, 1H), 8.63 (dd, J=5.1, 0.7Hz, 1H), 8.29-8.21 (m, 1H), 8.04-7.88 (m, 5H), 7.52-7.43 (m, 2H), 7.37(dd, J=5.2, 1.5 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 5.32-5.09 (m, 1H),4.57-4.38 (m, 2H), 4.20 (dd, J=9.9, 7.1 Hz, 1H), 3.80-3.57 (m, 2H),2.48-2.35 (m, 1H), 2.10 (dddd, J=42.5, 13.9, 10.0, 3.4 Hz, 1H).

Example 179 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-(methylamino)-6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

A mixture of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-[2-fluoro-6-(trifluoromethyl)-3-pyridyl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide(80 mg, 0.15 mmol) and methylamine in tetrahydrofuran (1.0 mL, 2.0 mmol,2 mol/L) in dimethyl sulfoxide (2 mL) was heated in a sealed vial at 80°C. for 3 hours. The mixture was degassed in vacuum and submitted for aRP HPLC purification to afford 46 mg (56%) of the title compound.

1H NMR (400 MHz, DMSO-d6) δ 9.34 (q, J=4.8 Hz, 1H), 8.96 (t, J=6.0 Hz,1H), 8.63 (dd, J=5.2, 0.7 Hz, 1H), 8.28-8.21 (m, 1H), 8.05-7.95 (m, 3H),7.52-7.43 (m, 2H), 7.39 (dd, J=5.2, 1.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H),5.32-5.10 (m, 1H), 4.56-4.39 (m, 2H), 4.20 (dd, J=9.9, 7.1 Hz, 1H),3.80-3.56 (m, 2H), 2.98 (d, J=4.7 Hz, 3H), 2.42 (dddd, J=20.0, 14.7,6.6, 2.0 Hz, 1H), 2.22-1.97 (m, 1H).

Example 180 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.63-9.57 (s, 2H), 9.11-9.04 (t, J=5.9 Hz, 1H),8.81-8.74 (d, J=1.3 Hz, 1H), 8.28-8.21 (d, J=5.7 Hz, 1H), 8.06-7.99 (m,2H), 7.52-7.44 (m, 2H), 5.30-5.11 (m, 1H), 4.60-4.50 (d, J=5.8 Hz, 2H),4.27-4.19 (dd, J=10.0, 7.1 Hz, 1H), 3.76-3.57 (m, 2H), 2.47-2.36 (m,1H), 2.21-2.00 (m, 1H)., LCMS (ESI) m/z:546.2 [M+H]+

Example 181 Preparation of(1R,5S)-4-(4-fluorophenyl)sulfonyl-N-[[3-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-azabicyclo[3.1.0]hexane-5-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.47-9.39 (s, 2H), 8.75-8.68 (dd, J=6.8, 5.3Hz, 1H), 7.95-7.87 (m, 2H), 7.82-7.77 (t, J=1.5 Hz, 1H), 7.76-7.69 (ddd,J=9.8, 2.3, 1.4 Hz, 1H), 7.56-7.48 (m, 2H), 7.44-7.36 (ddd, J=9.7, 2.3,1.3 Hz, 1H), 4.70-4.59 (dd, J=16.0, 6.8 Hz, 1H), 4.40-4.27 (dd, J=16.2,5.4 Hz, 1H), 3.74-3.62 (ddd, J=10.5, 9.0, 3.1 Hz, 1H), 2.99-2.87 (dt,J=10.4, 8.3 Hz, 1H), 2.24-2.10 (dtd, J=12.6, 8.9, 5.7 Hz, 1H), 1.87-1.72(m, 2H), 1.50-1.43 (dd, J=9.0, 5.9 Hz, 1H), 0.31-0.22 (t, J=5.9 Hz,1H)., LCMS (ESI) m/z:539.2 [M+H]+

Example 182 Preparation of(1R,5S)-4-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-4-azabicyclo[3.1.0]hexane-5-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.40-9.35 (s, 2H), 8.71-8.66 (dd, J=6.8, 5.2Hz, 1H), 8.10-8.04 (dd, J=7.2, 2.4 Hz, 1H), 7.95-7.85 (m, 3H), 7.56-7.47(m, 2H), 7.47-7.40 (dd, J=9.9, 8.6 Hz, 1H), 4.75-4.64 (dd, J=16.1, 6.8Hz, 1H), 4.36-4.26 (dd, J=16.1, 5.3 Hz, 1H), 3.74-3.62 (ddd, J=10.6,9.2, 3.1 Hz, 1H), 3.00-2.88 (dt, J=10.5, 8.5 Hz, 1H), 2.24-2.11 (dtd,J=13.0, 9.1, 5.9 Hz, 1H), 1.88-1.74 (m, 2H), 1.52-1.42 (dd, J=9.0, 5.9Hz, 1H), 0.33-0.23 (t, J=6.0 Hz, 1H)., LCMS (ESI) m/z:539.2 [M+H]+

Example 183 Preparation of(1S,2S,5R)-N-(2-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-3-((4-fluorophenyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide.

Step 1: tert-butyl(1R,4S,5S)-4-[(5-bromo-2-fluoro-phenyl)methylcarbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate3

To a solution of(1R,4S,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-4-carboxylicacid 1 (31 mg, 0.13 mmol), (5-bromo-2-fluoro-phenyl)methanaminehydrochloride 2 (36 mg, 0.15 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DMF(0.5 mL) was added HATU (63.5 mg, 0.16 mmol). The reaction mixture wasstirred for 1 h at room temperature. The resulting mixture was dilutedwith ethyl acetate, washed with water, brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column, eluting withethyl acetate/Heptane (1:1) to afford the compound 3 (30 mg, 53%) as aclear oil. LC/MS (ESI+): m/z 414 (M+H).

Step 2:(1R,4S,5S)-N-[(5-bromo-2-fluoro-phenyl)methyl]-3-azabicyclo[3.1.0]hexane-4-carboxamide4

A solution of tert-butyl(1R,4S,5S)-4-[(5-bromo-2-fluoro-phenyl)methylcarbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate3 (30 mg, 0.072 mmol) in dioxane (5 mL) was treated with 4N HCl indioxane (0.46 mL, 1.9 mmol). The reaction was stirred for 30 minutes atroom temperature. The resulting mixture was concentrated under reducedpressure to afford the crude product 4 which was used without furtherpurification. LC/MS (ESI+): m/z 314 (M+H).

Step 3:(1R,4S,5S)-N-[(5-bromo-2-fluoro-phenyl)methyl]-3-(4-fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-4-carboxamide6

(1R,4S,5S)-N-[(5-bromo-2-fluoro-phenyl)methyl]-3-azabicyclo[3.1.0]hexane-4-carboxamide4 (23 mg, 0.07 mmol) in DCM (1 mL) was treated with Et₃N (0.2 mL, 1.5mmol) followed by 4-fluorobenzenesulfonyl chloride 5 (17 mg, 0.09 mmol).The reaction was stirred for overnight at room temperature. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel, eluting with ethylacetate/heptane (1:1) to afford the compound 6 (26 mg, 75%) as a clearoil. LC/MS (ESI+): m/z 472 (M+H).

Step 4:(1R,4S,5S)-3-(4-fluorophenyl)sulfonyl-N-[[2-fluoro-5-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-3-azabicyclo[3.1.0]hexane-4-carboxamide

To a microwave vial was added(1R,4S,5S)-N-[(5-bromo-2-fluoro-phenyl)methyl]-3-(4-fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-4-carboxamide6 (35 mg, 0.07 mmol), [5-(trifluoromethyl)pyrimidin-2-yl]boronic acid(15.7 mg, 0.08 mmol), cesium carbonate 1 M in water (0.10 mL, 0.10mmol), Pd(dppf)Cl₂ (0.1 equiv., 0.01 mmol) and acetonitrile (0.8 mL).The reaction mixture was purged with nitrogen gas for 3 minutes and thenheated to 140° C. in the microwave for 30 minutes. Upon cooling to roomtemperature, the resulting mixture was filtered through a thin layer ofcelite, washed with water and extracted with ethyl acetate. The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel, eluting with ethyl acetate/heptane (3:1) to afford the titlecompound (24 mg, 60%) as a white solid. LC/MS (ESI+): m/z 539.2 (M+H).

1H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 2H), 8.77 (t, J=5.9 Hz, 1H),8.02-7.75 (m, 4H), 7.57-7.28 (m, 3H), 4.60-4.31 (m, 2H), 4.22 (s, 1H),3.72 (td, J=9.9, 3.6 Hz, 1H), 3.47 (d, J=10.4 Hz, 1H), 1.69-1.40 (m,2H), 0.60-0.45 (m, 1H), -0.82 (dt, J=5.1, 4.0 Hz, 1H).

Example 184 Preparation of(2S,4R)-N-([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of (2,5-dichloropyridin-4-yl)methanol

A solution of 2,5-dichloropyridine-4-carboxylic acid (2.00 g, 10.417mmol, 1.0 equiv) and BH₃-THF (30 mL, 3.0 equiv, 1 mol/L in THF) intetrahydrofuran (100 mL) was stirred for 30 min at 0° C. and 2 h at roomtemperature. The reaction was then quenched by water, extracted ethylacetate, washed with brine and concentrated under vacuum. The residuewas purified by a silica gel column eluting with ethyl acetate/petroleumether (1:3) to afford the title compound (1.5 g, 81%) as a white solid.

Step 2: Preparation of2-[(2,5-dichloropyridin-4-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (3.18 g, 15.726 mmol, 2.0 equiv) was added dropwise into a solutionof (2,5-dichloropyridin-4-yl)methanol (1.40 g, 7.864 mmol, 1.0 equiv),PPh₃ (4125.47 mg, 15.729 mmol, 2.0 equiv), and2,3-dihydro-1H-isoindole-1,3-dione (1735.66 mg, 11.797 mmol, 1.5 equiv)in tetrahydrofuran (50 mL) at 0° C. under nitrogen. The resultingsolution was stirred for 2 h at 0° C. and quenched by water. Theresulting solution was extracted with ethyl acetate, washed with brine,dried over Na₂SO₄, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:5) to afford the title compound (1.4 g, 58%) as a yellow solid.

Step 3: Preparation of2-([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

A mixture of2-[(2,5-dichloropyridin-4-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(1.40 g, 4.558 mmol, 1.0 equiv),5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(1.25 g, 4.561 mmol, 1.0 equiv), Pd(dppf)Cl₂ (330 mg, 0.451 mmol, 0.1equiv), and potassium carbonate (1.89 g, 13.675 mmol, 3.000 equiv) indioxane (100 mL)/water(5 mL) was stirred for 12 h at 60° C. undernitrogen. The reaction mixture was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withdichloromethane/petroleum ether (20:1) to afford the title compound (700mg, 37%) as a white solid.

Step 4: Preparation of[5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine

A mixture of2-([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(300.00 mg, 0.716 mmol, 1.0 equiv) and NH₂NH₂.H₂O (358.64 mg, 7.164mmol, 10.0 equiv) in methanol (20 mL) was stirred for 12 h at 50° C. Thereaction mixture was concentrated under vacuum. The solution was dilutedwith ethyl acetate and the solids were filtered out. The solution wasconcentrated under vacuum to afford the title compound (200 mg, 97%) asa gray solid.

Step 5: Preparation of tert-butyl(2S,4R)-2-[([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(161.60 mg, 0.693 mmol, 1.0 equiv), DIEA (268.64 mg, 2.079 mmol, 3.0equiv), and HATU (316.14 mg, 0.831 mmol, 1.2 equiv) in DMF (5 mL) wasstirred for 30 min at room temperature.[5-Chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine(200.00 mg, 0.693 mmol, 1.0 equiv) was then added to the solution. Theresulting solution was stirred for 12 h at room temperature. Thereaction mixture was diluted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:3) to afford the title compound (250 mg, 72%)as a white solid.

Step 6: Preparation of(2S,4R)-N-((5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,4R)-2-[([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(250 mg, 0.496 mmol, 1.000 equiv) and saturated HCl in dioxane(20 mL)was stirred for 12 h at room temperature. The reaction mixture wasconcentrated under vacuum. This resulted in the title compound (200 mg,100%) as a white solid.

Step 7: Preparation of(2S,4R)-N-([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A solution of(2S,4R)-N-((5-chloro-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (300.00 mg, 0.743 mmol, 1.0 equiv), triethylamine (225.56mg, 2.229 mmol, 3.0 equiv), and 4-fluorobenzene-1-sulfonyl chloride(289.20 mg, 1.486 mmol, 2.0 equiv) in dichloromethane (20 mL) wasstirred for 12 h at room temperature. The reaction mixture was thenquenched by water, extracted with dichloromethane, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:1) to afford the title compound (33.5 mg, 8%)as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.65 (s, 2H), 8.69 (s, 1H), 8.18 (s, 1H),7.91-7.88 (m, 2H), 7.41 (s, 1H), 7.29-7.23 (m, 2H), 5.15-4.96 (m, 2H),4.45-4.31 (m, 2H), 3.95-3.60 (m, 2H), 2.70-2.57 (m, 1H), 2.15-2.07 (m,1H).

Example 185 Preparation of5-fluoro-N-((5-fluoro-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)-2-(4-fluorophenylsulfonyl)-2-aza-bicyclo[2.2.1]heptane-3-carboxamide.

A solution of5-fluoro-2-[(4-fluorobenzene)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylicacid and6-fluoro-2-[(4-fluorobenzene)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (150 mg, 0.473 mmol, 1.74 equiv),[5-fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine(74 mg, 0.272 mmol, 1.00 equiv), DIEA (121 mg, 0.936 mmol, 3.44 equiv),and HATU (270 mg, 0.710 mmol, 2.61 equiv) in tetrahydrofuran (20 mL) wasstirred for 12 h at room temperature. The mixture was diluted with waterand extracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:15). This resulted in the titlecompound (6.7 mg, 4%) as a white solid. t_(R)=2.09 min (Lux Cellulose-4,0.46×5 cm, 3 μm, Hex:EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CD₃OD) δ 9.58 (s, 2H), 8.59 (s, 1H), 8.28 (d, J=5.7 Hz,1H), 8.04-8.00 (m, 2H), 7.34-7.29 (m, 2H), 5.18-5.00 (m, 1H), 4.77-4. 51(m, 2H), 4.44 (s, 1H), 4.23 (s, 1H), 3.01 (d, J=3.9 Hz, 1H), 2.25 (d,J=10.8 Hz, 1H), 1.90-1.77 (m, 1H), 1.57 (d, J=11.4 Hz, 1H), 1.46-1.28(m, 1H).

6-Fluoro-N-([5-fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2-[(4-fluorobenzene)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide(7.1 mg, 5%) was also isolated as a white solid. t_(R)=2.76 min (LuxCellulose-4, 0.46×5 cm, 3 μm, Hex:EtOH=50:50, 1.0 ml/min).

¹H NMR (300 MHz, CD₃OD) δ 9.58 (s, 2H), 8.60 (s, 1H), 8.28 (d, J=5.7 Hz,1H), 8.04-8.00 (m, 2H), 7.34-7.26 (m, 2H), 5.19-4.99 (m, 1H), 4.77-4.51(m, 2H), 4.44 (s, 1H), 4.23 (s, 1H), 3.02 (d, J=4.2 Hz, 1H), 2.25 (d,J=10.2 Hz, 1H), 2.00-1.77 (m, 1H), 1.57 (d, J=11.4 Hz, 1H), 1.41-1.21(m, 1H).

The F position (5-F or 6-F) for the above two position isomers wasarbitrary assigned. The 2-proline stereochemistry is as shown.

Example 186 Preparation of(2S,5S)-1-(4-fluorophenylsulfonyl)-5-methyl-N-((2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

A mixture of Pd(dppf)Cl₂ (1.15 g, 1.572 mmol, 0.10 equiv), potassiumcarbonate (4.35 g, 31.475 mmol, 2.00 equiv),2-[(2-bromopyridin-4-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (5 g,15.77 mmol, 1.00 equiv), and bis(propan-2-yl)[2-(trifluoromethyl)pyrimidin-5-yl]boron ate (4.35 g, 15.757 mmol, 1.00equiv) in dioxane (80 mL)/water (8 mL) was stirred for 12 h at 70° C.under nitrogen. The solids were filtered out and the filtrate wasdiluted in water. The aqueous layer was extracted with ethyl acetate.The pH value of the aqueous solution was adjusted to 3-4 with 1N HCl.The resulting solution was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (10g, crude) as a yellow solid.

Step 2: Preparation of[2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine

A solution of2-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(10 g, 26.021 mmol, 1.00 equiv) and NH₂NH₂.H₂O (13 g, 259.686 mmol, 9.98equiv) in ethanol (150 mL) was stirred for 12 h at 80° C. The resultingmixture was concentrated under vacuum. The reaction was diluted inwater. The pH value of the aqueous solution was adjusted to 3-4 with 1NHCl. The resulting solution was extracted with ethyl acetate. The pHvalue of the solution was adjusted to 8 with sodium bicarbonate. Theresulting solution was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (1 g,crude) as a yellow solid.

Step 3: Preparation of(2S,5S)-1-(4-fluorophenylsulfonyl)-5-methyl-N-((2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide

A solution of(2S,5S)-1-[(4-fluorobenzene)sulfonyl]-5-methylpyrrolidine-2-carboxylicacid (140 mg, 0.487 mmol, 0.67 equiv), DIEA (189 mg, 1.462 mmol, 2.0equiv), HATU (222 mg, 0.584 mmol, 0.8 equiv), and[2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine (186 mg,0.732 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was stirred for30 min at 25° C. The mixture was diluted with water and extracted withethyl acetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/1). The crude product (568 mg) was purified by Prep-HPLC toafford the title compound (136 mg) as a white solid.

¹I-INMR (300 MHz, CDCl₃) δ 9.59 (s, 2H), 8.74-8.72 (s, 1H), 7.95-7.89(m, 3H), 7.54 (s, 1H), 7.36-7.26 (m, 3H), 4.94-4.86 (m, 1H), 4.48-4.41(m, 1H), 4.19-4.15 (m, 1H), 3.73-3.67 (m, 1H), 2.22-2.15 (s, 1H),1.81-1.71 (m, 2H), 1.70-1.46 (m, 4H).

Example 187 Preparation of(2S,4R)-4-fluoro-N-(2-fluoro-5-(2-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1-((4-fluorophenyl)sulfonyl)-4-methylpyrrolidine-2-carboxamide.

Preparation of the title compound follow the same general procedure asExample 52.

MS-ESI: [M+H]⁺559.2

¹H NMR (400 MHz, DMSO) δ 9.36 (s, 2H), 8.89 (t, J=5.9 Hz, 1H), 8.00-7.93(m, 3H), 7.92-7.87 (m, 1H), 7.52-7.39 (m, 3H), 4.47 (d, J=5.8 Hz, 2H),4.27-4.18 (m, 1H), 3.70-3.45 (m, 2H), 2.45-2.30 (m, 1H), 2.14-1.93 (m,1H), 1.37 (d, J=20.7 Hz, 3H).

Example 188 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[2-methoxy-6-[2-(trifluoromethyl)pyrimidin-5-yl]-4-pyridyl]methyl]pyrrolidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 48.

1H NMR (400 MHz, DMSO) δ 9.69-9.63 (s, 2H), 9.00-8.93 (t, J=6.0 Hz, 1H),8.03-7.96 (m, 2H), 7.82-7.79 (d, J=1.1 Hz, 1H), 7.52-7.44 (m, 2H),6.97-6.92 (q, J=1.0 Hz, 1H), 5.29-5.10 (d, J=52.3 Hz, 1H), 4.53-4.36 (m,2H), 4.23-4.16 (dd, J=10.0, 7.1 Hz, 1H), 4.03-3.98 (s, 3H), 3.75-3.58(m, 2H), 2.46-2.36 (m, 1H), 2.21-1.99 (m, 1H)., LCMS (ESI) m/z:558.2[M+H]+

Example 189 Preparation of(2S,4R)-N-([5-cyano-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of(2S,4R)-N-([5-cyano-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-N-([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide(150 mg, 0.267 mmol, 1.0 equiv), Zn(CN)₂ (32 mg, 0.272 mmol, 1.02\equiv), Pd₂(dba)₃.CHCl₃ (28 mg, 0.027 mmol, 0.10 equiv), and dppf (45mg, 0.081 mmol, 0.31 equiv) in DMF (15 mL) was irradiated with microwavefor 1 h at 150° C. under nitrogen. The reaction mixture was diluted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). The crudeproduct (100 mg) was re-purified by Flash-Prep-HPLC to afford the titlecompound (44.5 mg, 30%) as a pink solid.

¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 2H), 8.96 (s, 1H), 8.32 (s, 1H),7.92-7.88 (m, 2H), 7.52-7.49 (m, 1H), 7.29-7.24 (m, 2H), 5.17-5.01 (m,2H), 4.58-4.52 (m, 1H), 4.34-4.30 (m, 1H), 3.91-3.65 (m, 2H), 2.66-2.60(m, 1H), 2.25-2.12 (m, 1H).

Example 190 Preparation of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine.

2-Chloro-6-(trifluoromethyl)pyridin-3-amine (3 g, 15.263 mmol, 1.000equiv) was added into a mixture of CuBr₂ (6.8 g, 30.445 mmol, 2.000equiv) and t-BuONO (3.1 g, 30.062 mmol, 2.000 equiv) in CH₃CN (100 mL).The resulting solution was stirred for 2 h at room temperature. Thereaction mixture was diluted with water, extracted with diethyl ether,dried over sodium sulfate, and concentrated under vacuum. This resultedin the title compound (3 g, 75%) as a brown liquid.

Step 2: Preparation of3-bromo-2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridine

A mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (3 g, 11.519mmol, 1.00 equiv) and 1-methoxy-2-(sodiooxy)ethane (1.2 g, 12.235 mmol,1.10 equiv) in 2-methoxyethan-1-ol (30 mL) was stirred overnight at roomtemperature. The reaction mixture was then quenched with water,extracted with diethyl ether, dried over sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (4 g) asa red liquid which was used for the next step without any furtherpurification.

Step 3: Preparation of methyl3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]benzoate

A mixture of 3-bromo-2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridine(1.6 g, 5.33 mmol, 1.0 equiv), methyl3-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.5 g, 5.36mmol, 1.0 equiv), potassium carbonate (1.5 g, 10.85 mmol, 2.0 equiv),and Pd(dppf)Cl₂ (390 mg, 0.533 mmol, 0.10 equiv) in dioxane (50 mL) wasstirred overnight at 90° C. under nitrogen. The reaction mixture wasdiluted with water, extracted with ethyl acetate, dried over sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:10) toafford the title compound (1.9 g, 95%) as brown oil.

Step 4: Preparation of[3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methanol

LiAlH₄ (360 mg, 9.485 mmol, 2.000 equiv) was added in several batchesinto a solution of methyl3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]benzoate(1.8 g, 4.822 mmol, 1.000 equiv) in tetrahydrofuran (50 mL) at 0° C.under nitrogen. The resulting solution was stirred for 2 h at 0° C. andquenched by water. The solids were filtered out and the liquid wasconcentrated under vacuum. This resulted in 1.5 g of the title compoundas a light yellow solid.

Step 5: Preparation of2-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione.

DIAD (1.6 g, 7.913 mmol, 2.000 equiv) was added dropwise into a solutionof[3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methanol(1.4 g, 4.055 mmol, 1.000 equiv), 2,3-dihydro-1H-isoindole-1,3-dione(1.2 g, 8.156 mmol, 2.000 equiv), and PPh₃ (2.1 g, 8.007 mmol, 2.000equiv) in tetrahydrofuran (50 mL) at 0° C. under nitrogen. The resultingsolution was stirred for 2 h at room temperature and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:5) to afford the title compound (1.3 g,68%) as a white solid.

Step 6: Preparation of[3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methanamine

A mixture of2-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(1.2 g, 2.53 mmol, 1.0 equiv) and NH₂NH₂.H₂O (2 mL, 41.150 mmol, 10.0equiv) in methanol (10 mL) was stirred overnight at room temperature.The reaction mixture was concentrated under vacuum, diluted with water,extracted with dichloromethane, dried over sodium sulfate, andconcentrated under vacuum. This resulted in the title compound (750 mg,86%) as light yellow oil.

Step 7: Preparation of tert-butyl(4R)-4-fluoro-2-[([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(68 mg, 0.292 mmol, 1.000 equiv), HATU (132 mg, 0.347 mmol, 1.200equiv),[3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methanamine(100 mg, 0.290 mmol, 1.000 equiv), and DIEA (75 mg, 0.580 mmol, 2.000equiv) in N,N-dimethylformamide (5 mL) was stirred for 2 h at roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in the title compound (180 mg) as lightyellow oil.

Step 8: Preparation of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(4R)-4-fluoro-2-[([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)carbamoyl]pyrrolidine-1-carboxylate(180 mg, 0.322 mmol, 1.000 equiv) and hydrogen chloride in dioxane (10mL) was stirred overnight at room temperature. The product wasprecipitated by the addition of hexane. The solids were collected byfiltration to afford the title compound (160 mg) as a brown solid.

Step 9: Preparation of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

A solution of(2S,4R)-4-fluoro-N-([3-fluoro-5-[2-(2-methoxyethoxy)-6-(trifluoromethyl)pyridin-3-yl]phenyl]methyl)pyrrolidine-2-carboxamidehydrochloride (160 mg, 0.32 mmol, 1.000 equiv), DIEA (125 mg, 0.967mmol, 3.0 equiv), and 4-fluorobenzene-1-sulfonyl chloride (69 mg, 0.355mmol, 1.1 equiv) in dichloromethane (20 mL) was stirred for 2 h at roomtemperature. The reaction mixture was concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:1). The crude product was purified byPrep-HPLC to afford the tile compound (50.3 mg, 25%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.79-7.84 (m, 3H), 7.40-7.22 (m, 6H), 7.11 (d,J=12.0 Hz, 1H) 5.12-4.99 (d, J=52.0 Hz, 1H), 4.68-4.60 (m, 3H),4.53-4.48 (dd, J=15.2 Hz, J=5.2 Hz, 1H), 4.29 (t, J=8.4 Hz, 1H),3.96-3.87 (m, 1H), 3.78 (t, J=4.8 Hz, 1H), 3.70-3.56 (m, 1H), 3.43 (s,3H), 2.60-2.47 (m, 1H), 2.40-2.20 (m, 1H).

Example 191 Preparation of(2R,3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of5-(2,6-dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine

A mixture of 2,6-dichloro-4-iodopyridine (8.61 g, 31.43 mmol, 1.00equiv),5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(7.85 g, 28.64 mmol, 1.00 equiv), potassium carbonate (11.9 g, 86.10mmol, 1.00 equiv), and Pd(dppf)Cl₂(1.05 g, 1.43 mmol, 1.00 equiv) indioxane (150 mL)/water(10 mL) was stirred for 12 h at 60° C. undernitrogen. The reaction solution was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1:20) to afford the title compound (6 g,65%) as an off-white solid.

Step 2: Preparation of5-(2,6-dimethylpyridin-4-yl)-2-(trifluoromethyl)pyrimidine

A mixture of 5-(2,6-dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine(1.7 g, 5.78 mmol, 1.00 equiv), Pd(dppf)Cl₂ (423 mg, 0.57 mmol, 0.10equiv), and dimethylzinc (21.7 mL, 1.2 M in toluene, 4.50 equiv) indioxane (100 mL) was stirred for 12 h at 60° C. under nitrogen. Theresulting mixture was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1:5) to afford the title compound (770 mg, 53%) as a light yellowsolid.

Step 3: Preparation of2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-1-ium-1-olate

A solution of m-CPBA (578 mg, 3.34 mmol, 1.10 equiv) in ethyl acetate(5mL) was added dropwise with stirring into the solution of5-(2,6-dimethylpyridin-4-yl)-2-(trifluoromethyl)pyrimidine (770 mg, 3.04mmol, 1.00 equiv) in dichloromethane (50 mL) at 0° C. The resultingsolution was stirred for 12 h at room temperature. The reaction was thenquenched with saturated of sodium bicarbonate, extracted with ethylacetate, washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with dichloromethane/methanol (50/1) to afford the titlecompound (750 mg, 92%) as a light yellow solid.

Step 4: Preparation of[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methylacetate

A solution of2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-1-ium-1-olate(750mg, 2.78 mmol, 1.00 equiv) in acetic anhydride (15 mL) was heated toreflux for 1 h. The reaction mixture was cooled and poured into icewater. The pH value of the solution was adjusted to 8 with saturated ofsodium bicarbonate, extracted with ethyl acetate, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting withdichloromethane/methanol (20/1) to afford the title compound (650 mg,75%) as an off-white solid.

Step 5: Preparation of[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanol

A solution of[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methylacetate (650 mg, 2.08 mmol, 1.00 equiv) and hydrogen chloride (15 mL,493.67 mmol, 1.00 equiv) in ethanol (15 mL) was heated to reflux for 2h. The reaction solution was diluted with water. The pH value of thesolution was adjusted to 8 with saturated of sodium bicarbonate,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with dichloromethane/methanol (20/1) toafford the title compound (340 mg, 60%) as a light yellow solid.

Step 6: Preparation of2-([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (511 mg, 2.52 mmol, 2.00 equiv) was added to the solution of[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanol(340 mg, 1.26 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindole-1,3-dione (372mg, 2.52 mmol, 2.00 equiv), and PPh₃ (662 mg, 2.52 mmol, 1.99 equiv) inTHF (50 mL) dropwise at 0° C. The resulting solution was stirred for 12h at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by a silica gel column eluting withacetate/petroleum ether (1/1) to afford the title compound (300 mg, 60%)as a white solid.

Step 7: Preparation of6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-amine

A solution of2-[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione(600 mg, 1.56 mmol, 1.00 equiv) and NH₂NH₂.H₂O (754 mg, 15.06 mmol, 9.64equiv) in methanol (15 mL) was stirred for 12 h at 25° C. The resultingmixture was concentrated under vacuum. The residue was dissolved withethyl acetate and the solid were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 686 mg (crude) of the titlecompound as oil.

Step 8: Preparation of tert-butyl(2S,3R)-3-hydroxy-2-[([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid(97 mg, 0.41 mmol, 1.19 equiv), DIEA (136 mg, 1.05 mmol, 3.00 equiv),HATU (213 mg, 0.56 mmol, 1.59 equiv), and[6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanamine(94mg, 0.35 mmol, 1.00 equiv) in DMF (5 mL) was stirred for 30 min at 25°C. The reaction solution was diluted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in 168 mg (crude) of the title compound as asolid.

Step 9: Preparation of tert-butyl(2R,3S)-3-fluoro-2-[([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (112 mg, 0.69 mmol, 1.99 equiv) was added to a solution oftert-butyl(2S,3R)-3-hydroxy-2-[([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(168 mg, 0.34 mmol, 1.00 equiv) in dichloromethane (20 mL) dropwise at0° C. and the reaction was stirred for 2 h at room temperature. Thereaction was then quenched by sodium bicarbonate/water, extracted withof ethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder vacuum. This resulted in 65 mg (39%) of the title compound as awhite solid.

Step 10: Preparation of(2R,3S)-3-fluoro-N-((6-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2R,3S)-3-fluoro-2-[([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(65 mg, 0.13 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (5 mL) was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum to afford the titlecompound (120 mg) as a crude solid.

Step 11: Preparation of(2R,3S)-3-fluoro-1-[(4-fluorobenzene)sulfonyl]-N-([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamide

4-Fluorobenzene-1-sulfonyl chloride (84 mg, 0.43 mmol, 1.51 equiv) wasadded into the solution of(2R,3S)-3-fluoro-N-([6-methyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (120 mg, 0.28 mmol, 1.00 equiv) and TEA (87 mg, 0.86 mmol,3.00 equiv) in dichloromethane(20 mL). The reaction mixture was stirredfor 12 h at room temperature. The resulting solution was diluted withethyl acetate, washed with brine, dried over anhydrous sodium sulfateand concentrated under vacuum. This resulted in the title compound (24.4mg, 16%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 2H), 7.98-7.88 (m, 3H), 7.60-7.50 (m,1H), 7.34-7.23 (m, 2H), 6.91 (m, 1H), 5.39-5.22 (d, J=51.0 Hz, 1H),4.94-4.86 (m, 1H), 4.60-4.55 (m, 1H), 4.41-4.33 (m, 1H), 3.84-3.70 (m,1H), 3.33-3.24 (m, 1H), 2.72-2.62 (s, 3H), 2.20-1.95 (m, 2H).

Example 192 Preparation of(2S,4R)-N-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide.

Step 1: Preparation of5-(2,5-dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine

A mixture of 2,5-dichloro-4-iodopyridine (3.86 g, 14.09 mmol, 1.00equiv),5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine(4.26 g, 15.54 mmol, 1.10 equiv), potassium carbonate (5.83 g, 42.19mmol, 2.99 equiv), and Pd(dppf)Cl₂ (516 mg, 0.70 mmol, 0.05 equiv) indioxane (50 mL)/water (5 mL) was stirred for 12 h at 60° C. undernitrogen. The solids were filtered out. The filtrate was diluted withethyl acetate, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with acetate/petroleum ether (1/100) to afford the titlecompound (2.2 g, 53%) as a yellow solid.

Step 2: Preparation of methyl5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-2-carboxylate

A mixture of 5-(2,5-dichloropyridin-4-yl)-2-(trifluoromethyl)pyrimidine(2.19 g, 7.47 mmol, 1.00 equiv), Pd(dppf)Cl₂ (549 mg, 0.75 mmol, 0.10equiv), and TEA (2.27 g, 22.47 mmol, 3.00 equiv) in methanol (50 mL) wasstirred for 12 h at 60° C. under carbon monoxide. The reaction solutionwas diluted with ethyl acetate, washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with acetate/petroleum ether(1/100) to afford the title compound (1.2 g, 52%) as a pink solid.

Step 3: Preparation of5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-2-carbaldehyde

DIBAL-H (4.5 mL, 31.64 mmol, 3.00 equiv) was added to the solutionmethyl5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-2-carboxylate(482mg, 1.51 mol, 1.00 equiv) in dichloromethane (200 mL) dropwise at −78°C. under nitrogen, and stirred for 20 min at −78° C. The reaction wasthen quenched with methanol. The resulting solution was diluted withethyl acetate, washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with acetate/petroleum ether (1/20) to affordthe title compound 344 mg (crude) as a light yellow solid.

Step 4: Preparation of[5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanol

NaBH₄ (18 mg, 0.47 mmol, 0.39 equiv) was added into the solution of5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridine-2-carbaldehyde(344 mg, 1.19 mmol, 1.00 equiv) in methanol (200 mL) batch wise at −20°C. and stirred for 30 min. The reaction mixture was quenched withsaturated NH₄Cl, extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby a silica gel column eluting with acetate/petroleum ether (1/1) toafford the title compound (330 mg, 95%) as a brown solid.

Step 5: Preparation of2-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (490 mg, 2.42 mmol, 2.00 equiv) was added to a solution of[5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanol(350 mg, 1.20 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindole-1,3-dione (356mg, 2.42 mmol, 2.00 equiv), and PPh₃ (634 mg, 2.41 mmol, 2.00 equiv) intetrahydrofuran (200 mL) dropwise at 0° C. The resulting solution wasstirred for 12 hours at room temperature. The resulting solution wasdiluted with ethyl acetate, washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with acetate/petroleum ether(1/5) to afford the title compound 800 mg (crude) as yellow oil.

Step 6: Preparation of[5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanamine

A solution of2-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(800 mg, 1.91 mmol, 1.00 equiv), NH₂NH₂.H₂O (957 mg, 19.17 mmol, 10.00equiv) in methanol (60 mL) was stirred for 3 h at 60° C. The resultingmixture was concentrated under vacuum. The residue was dissolved withethyl acetate. The solids were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 700 mg (crude) of the titlecompound as yellow oil.

Step 7: Preparation of tert-butyl(2S,4R)-2-[([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(690 mg, 2.95 mmol, 1.23 equiv), HATU (1.091 g, 2.86 mmol, 1.20 equiv),DIEA (618 mg, 4.78 mmol, 2.00 equiv), and[5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanamine(690 mg, 2.39 mmol, 1.00 equiv) in DMF (15 mL) was stirred for 2 h atroom temperature. The resulting solution was diluted with ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with acetate/petroleum ether (1/5) to afford the titlecompound (800 mg, 66%) as a yellow solid.

Step 8: Preparation of(2S,4R)-N-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride

A mixture of(2S,4R)-2-[([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate(210 mg, 0.41 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (50 mL) was stirred for 12 hours at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 168 mg(92%) of the title compound as light yellow oil.

Step 9: Preparation of(2S,4R)-N-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]pyrrolidine-2-carboxamide

4-Fluorobenzene-1-sulfonyl chloride (180 mg, 0.92 mmol, 2.42 equiv) wasadded to the solution of(2S,4R)-N-([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)-4-fluoropyrrolidine-2-carboxamidehydrochloride (168 mg, 0.38 mmol, 1.00 equiv), and TEA (200 mg, 1.97mmol, 5.17 equiv) in dichloromethane (30 mL), and stirred for 4 h atroom temperature. The resulting solution was diluted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The crude product (200 mg) was purified by Prep-HPLC togive the title compound (32.3 mg, 15%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 2H), 8.73 (s, 1H), 7.87-7.84 (m, 2H),7.58 (s, 1H), 7.55 (s, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 5.12-4.99 (d,J=52.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.57-4.52 (m, 1H), 4.29-4.25 (t,J=8.4 Hz, 1H), 3.91-3.61 (m, 2H), 2.61-2.51 (m, 1H), 2.31-2.15 (m, 1H).

Example 193 Preparation of(2S,4R,5S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate

A solution of 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate(10 g, 40.77 mmol, 1.00 equiv), Imidazole (2.78 g, 40.83 mmol, 1.10equiv), and tert-butyl(chloro)dimethylsilane(6.7 g, 44.45 mmol, 1.10equiv) in DMF (100 mL) was stirred overnight at room temperature. Theresulting solution was diluted with ethyl acetate, washed with water andof brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withacetate/petroleum ether (1/8) to afford the title compound (16 g) ascolorless oil.

Step 2: Preparation of 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-1,2-dicarboxylate

A mixture of NaIO₄ (7.43 g, 34.73 mmol, 2.50 equiv) and ruthenium(IV)oxide (370 mg, 2.78 mmol, 0.20 equiv) in water (107 mL) was stirred for5 min at room temperature. To this was added the solution of1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (5g, 13.90 mmol, 1.00 equiv) in ethyl acetate (60 mL) and the reaction wasstirred for 3 h at room temperature. The resulting solution was dilutedwith ethyl acetate, washed with NaHSO₃/water and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with acetate/petroleum ether(1/8) to afford the title compound (3.3 g, 64%) as colorless oil.

Step 3: Preparation of methyl (2S,4S)-1-tert-butyl 2-methyl4-(tert-butyldimethylsilyloxy)-5-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate

Bromo(methyl)magnesium (3.48 mL, 87.55 mmol, 1.20 equiv) was added tothe solution of 1-tert-butyl 2-methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-1,2-dicarboxylate(3.25 g, 8.70 mmol, 1.00 equiv) in THF (50 mL) dropwise at −40° C. andstirred for 2 h at −40° C. The reaction was then quenched with saturatedNH₄C1, extracted with ethyl acetate, washed with water and of brine,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1/8) to afford the title compound (1.1 g, 32%)as light yellow oil.

Step 4: Preparation of methyl4-[(tert-butyldimethylsilyl)oxy]-5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate

A solution of methyl (2S,4S)-1-tert-butyl 2-methyl4-(tert-butyldimethylsilyloxy)-5-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate(6 g, 15.40 mmol, 1.00 equiv) and TFA (5 mL, 67.31 mmol, 1.00 equiv) indichloromethane (50 mL) was stirred for 5 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 6 g ofthe title compound as brown oil.

Step 5: Preparation of methyl(2S,4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-2-carboxylate

A mixture of methyl(2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate(6 g, 22.10 mmol, 1.00 equiv) and palladium carbon (500 mg) in methanol(100 mL) was stirred for 2 h at room temperature under H₂. The solidswere filtered out. The resulting mixture was concentrated under vacuum.This resulted in 5.6 g (93%) of as yellow oil.

Step 6: Preparation of 1-tert-butyl 2-methyl(2S,4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-1,2-dicarboxylate

A solution of methyl(2S,4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-2-carboxylate(5.5 g, 20.11 mmol, 1.00 equiv), TEA (8.13 g, 80.34 mmol, 4.00 equiv),4-dimethylaminopyridine (245 mg, 2.00 mmol, 0.10 equiv), di-tert-butyldicarbonate (13.16 g, 60.29 mmol, 3.00 equiv) in THF (250 mL) wasstirred overnight at 50° C. The resulting mixture was concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1/10) to afford the title compound (3 g,40%) as light yellow oil.

Step 7: Preparation of(2S,4S,5S)-1-[(tert-butoxy)carbonyl]-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-2-carboxylicacid

A solution of 1-tert-butyl 2-methyl(2S,4S,5S)-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-1,2-dicarboxylate(20 mg, 0.05 mmol, 1.00 equiv) and LiOH (3 mg, 0.12 mmol, 2.00 equiv) inmethanol (2 mL)/water (0.2 mL) was stirred for 5 h at 40° C. Theresulting solution was diluted with water. The pH value of the solutionwas adjusted to 4 with acetic acid. The resulting solution was extractedwith dichloromethane, dried over anhydrous sodium sulfate, andconcentrated under vacuum. This resulted in 20 mg (crude) of the titlecompound as yellow oil.

Step 8: Preparation of tert-butyl(2S,3S,5S)-3-[(tert-butyldimethylsilyl)oxy]-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,4S,5S)-1-[(tert-butoxy)carbonyl]-4-[(tert-butyldimethylsilyl)oxy]-5-methylpyrrolidine-2-carboxylicacid (400 mg, 1.11 mmol, 1.00 equiv), HATU (880 mg, 2.31 mmol, 1.50equiv), DIEA(600 mg, 4.64 mmol, 3.00 equiv), and2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-ylmethanamine(464 mg,1.82 mmol, 1.20 equiv) in DMF (10 mL) was stirred for 1 h at roomtemperature. The resulting solution was diluted with ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1/3) to afford thetitle compound (360 mg, 54%) as light yellow oil.

Step 9: Preparation of tert-butyl(2S,3S,5S)-3-hydroxy-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of tert-butyl(2S,3S,5S)-3-[(tert-butyldimethylsilyl)oxy]-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(360 mg, 0.60 mmol, 1.00 equiv) and TBAF (1.34 mL, 5.12 mmol, 1.00equiv) in THF (10 mL) was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (2/1) to afford the title compound (300 mg, crude) as a whitesolid.

Step 10: Preparation of tert-butyl(2S,3R,5S)-3-fluoro-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

DAST (424 mg, 2.63 mmol, 3.00 equiv) was added to the solution oftert-butyl(2S,3S,5S)-3-hydroxy-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(300 mg, 0.62 mmol, 1.00 equiv) in dichloromethane (10 mL) dropwise at0° C. and stirred overnight at room temperature. The reaction was thenquenched with water, extracted with dichloromethane, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (2/1) to afford the title compound (110 mg, 37%) as a light yellowsolid.

Step 11: Preparation of(2S,4R,5S)-4-fluoro-5-methyl-N-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride

A mixture of tert-butyl(2S,3R,5S)-3-fluoro-2-methyl-5-[([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(110 mg, 0.22 mmol, 1.00 equiv) and saturated hydrogen chloride in1,4-dioxane (20 mL) was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 105 mg(crude) of the title compound as a light yellow solid.

Step 12: Preparation of(2S,4R,5S)-4-fluoro-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide

4-Fluorobenzene-1-sulfonyl chloride (73 mg, 0.37 mmol, 1.20 equiv) wasadded to a solution of(2S,4R,5S)-4-fluoro-5-methyl-N-([2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamidehydrochloride (105 mg, 0.25 mmol, 1.00 equiv) and sodium bicarbonate(41.5 mg, 0.49 mmol, 2.00 equiv) in THF (8 mL)/water (8 mL). This wasstirred for 1 h at room temperature. The resulting solution wasextracted with ethyl acetate, washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct was purified by Prep-HPLC to give the title compound (16.9 mg,12%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 2H), 8.80 (s, 1H), 8.13 (s ,1H),7.93-7.90 (m, 2H), 7.54-7.51 (m, 2H), 7.28-7.25 (m, 1H), 5.03-4.99 (m,1H), 4.82-4.68 (d, J=51.6 Hz, 1H), 4.50-4.32 (m, 1H), 4.30-4.27 (m, 1H),4.15-4.08 (m, 1H), 2.65-2.55 (m, 1H), 2.39-2.23 (m, 1H), 1.48-1.38 (m,3H).

Example 194 Preparation of(2S)-1-(4-fluorophenyl)sulfonyl-5,5-dimethyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide.

Step 1: Following the HATU coupling procedure of Example 35, step 1:tert-butyl(5S)-2,2-dimethyl-5-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate (INT-194-2) (320 mg, 81%) was prepared from(2S)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidine-2-carboxylic acid(200 mg, 0.8 mmol) and[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methanamine (230 mg,0.9 mmol), DIPEA (0.4 mL, 2.5 mmol), HATU (383 mg, 0.99 mmol) in DMF (2mL). MS-ESI: [M+H]+480.5

Step 2: Following the boc removal procedure of Example 35, step 3:(2S)-5,5-dimethyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamidehydrochloride (INT-194-3) (250 mg, 81%) was prepared from tert-butyl(5S)-2,2-dimethyl-5-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methylcarbamoyl]pyrrolidine-1-carboxylate(387 mg, 0.8 mmol) and 4 N HCl in dioxane (2 mL, 8 mmol). MS-ESI:[M+H]⁺380.5

Step 3: Following the sulfonamide formation procedure of Example 35,step 4: The title compound 194(2S)-1-(4-fluorophenyl)sulfonyl-5,5-dimethyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide(162 mg, 37%) was prepared from(2S)-5,5-dimethyl-N-[[6-[6-(trifluoromethyl)-3-pyridyl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamidehydrochloride (INT194-3) (306 mg, 0.8 mmol), Et₃N (2.25 mL, 16 mmol),4-fluorobenzenesulfonyl chloride (188 mg, 0.97 mmol) in DCM (1 mL).MS-ESI: [M+H]⁺538.5

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J=2.1 Hz, 1H), 9.29 (d, J=1.3 Hz,1H), 8.81 (t, J=5.9 Hz, 1H), 8.73 (ddd, J=8.4, 2.3, 0.9 Hz, 1H), 8.17(d, J=1.3 Hz, 1H), 8.11-7.94 (m, 3H), 7.49-7.19 (m, 2H), 4.67-4.48 (m,2H), 4.39 (dd, J=17.4, 5.6 Hz, 1H), 2.24-2.10 (m, 1H), 2.02 (td, J=11.5,6.5 Hz, 1H), 1.84 (ddt, J=12.0, 6.1, 2.7 Hz, 1H), 1.71 (ddd, J=11.8,6.7, 2.9 Hz, 1H), 1.45 (s, 3H), 1.24 (s, 3H).

Example 195 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-[2-trifluoromethyl)pyrimidin-5-yl]-3-pyridyl]methyl]pyrrolidine-2-carboxamide.

Step 1: Following the HATU coupling procedure of Example 35, step 1:tert-butyl(2S,4R)-2-[(5-bromo-3-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(INT-195-2) (280 mg, 32%) was prepared from(2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(500 mg, 2.1 mmol) and (5-bromo-3-pyridyl)methanamine (441 mg, 2.4mmol), DIPEA (1.1 mL, 6.4 mmol), HATU (998 mg, 2.6 mmol) in DMF (2 mL).MS-ESI: [M+H]⁺403.3

Step 2: Following the boc removal procedure of Example 35, step 3:(2S,4R)-N-[(5-bromo-3-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(INT-195-3) (210 mg, 100%) was prepared from tert-butyl(2S,4R)-2-[(5-bromo-3-pyridyl)methylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylate(INT-195-2) (280 mg, 0.7 mmol) and 4 N HCl in dioxane (1.7 mL, 7 mmol).MS-ESI: [M+H]⁺303.3

Step 3: Following the sulfonamide formation procedure of Example 35,step 4:(2S,4R)-N-[(5-bromo-3-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(INT-195-4) (200 mg, 63%) was prepared from(2S,4R)-N-[(5-bromo-3-pyridyl)methyl]-4-fluoro-pyrrolidine-2-carboxamide(INT-195-3) (210 mg, 0.7 mmol), Et₃N (1.9 mL, 14 mmol),4-fluorobenzenesulfonyl chloride (162 mg, 0.8 mmol) in DCM (1 mL).MS-ESI: [M+H]⁺461.3

Step 4: Following the same Suzuki coupling procedure of Example 42, step1: The title compound 195(2S,4R)-4-fluoro-1-(4-fluorophenyl)sulfonyl-N-[[5-[2-(trifluoromethyl)pyrimidin-5-yl]-3-pyridyl]methyl]pyrrolidine-2-carboxamide(62 mg, 54%) was prepared from(2S,4R)-N-[(5-bromo-3-pyridyl)methyl]-4-fluoro-1-(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide(INT-195-4) (100 mg, 0.22 mmol),[5-(trifluoromethyl)pyrimidin-2-yl]boronic acid (46 mg, 0.24 mmol),cesium carbonate 1 M in water (0.3 mL, 0.3 mmol), Pd(dppf)Cl₂ (18 mg,0.02 mmol) in acetonitrile (1 mL). MS-ESI: [M+H]⁺528.5

¹H NMR (400 MHz, DMSO-d₆) δ 9.53-9.37 (m, 2H), 9.07-8.97 (m, 1H), 8.70(d, J=2.0 Hz, 1H), 8.23 (t, J=2.2 Hz, 1H), 8.05-7.87 (m, 2H), 7.56-7.33(m, 2H), 5.19 (d, J=52.8 Hz, 1H), 4.63-4.33 (m, 2H), 4.25-4.09 (m, 1H),3.78-3.67 (m, 1H), 3.64 (dd, J=14.9, 2.4 Hz, 1H), 2.49-2.28 (m, 1H),2.07 (s, 1H).

Example 196 Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((5-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide.

Step 1: Preparation of2-[(2-bromo-5-fluoropyridin-4-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione

DIAD (1.57 g, 7.76 mmol, 2.00 equiv) was added dropwise into a solutionof 2,3-dihydro-1H-isoindole-1,3-dione (690 mg, 4.69 mmol, 1.20 equiv),(2-bromo-5-fluoropyridin-4-yl)methanol (800.00 mg, 3.88 mmol, 1.00equiv), and PPh₃ (2.04 g, 7.78 mmol, 2.00 equiv) in tetrahydrofuran (40mL) at 0° C. under nitrogen. The resulting solution was stirred for 12 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by a silica gel column with ethylacetate/petroleum ether (1:5) to afford the title compound (500 mg, 38%)as a white solid.

Step 2: Preparation of2-([5-fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole -1,3-dione

A mixture of Pd(dppf)Cl₂ (196 mg, 0.268 mmol, 0.10 equiv), potassiumcarbonate (741 mg, 5.362 mmol, 2.0 equiv),2-[(2-bromo-5-fluoropyridin-4-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione(900 mg, 2.686 mmol, 1.0 equiv), and bis(propan-2-yl)[2-(trifluoromethyl)pyrimidin-5-yl]boronate (3.3 g, 11.954 mmol, 4.45equiv) in 1,4-dioxane (25 mL)/water(2.5 mL) was stirred for 12 h at 70°C. under nitrogen. The mixture was diluted with water and extracted withethyl acetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by a silica gel column eluting with ethyl acetate/petroleumether (1/5) to afford the title compound (1 g, 91%) as a yellow solid.

Step 3: Preparation of2-[([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]benzoicacid

A solution of2-([5-fluoro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)-2,3-dihydro-1H-isoindole-1,3-dione(250 mg, 0.621 mmol, 1.00 equiv) and MeONa (340 mg, 6.294 mmol, 10.128equiv) in methanol (50 mL) was stirred for 5 h at 85° C. The resultingmixture was concentrated under vacuum and diluted with water. The pHvalue of the solution was adjusted to 3-5 with 1N hydrogen chloride. Theresulting solution was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. This resulted in the title compound (250mg, 93%) as a white solid.

Step 4: Preparation of[5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine

A solution of2-[([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]benzoicacid (250 mg, 0.578 mmol, 1.00 equiv) and NH₂NH₂.H₂O (300 mg, 5.993mmol, 10.36 equiv) in ethanol (30 mL) was stirred for 12 h at 80° C. Theresulting mixture was concentrated under vacuum and diluted with water.The pH value of the solution was adjusted to 3-5 with 1N hydrogenchloride. The resulting solution was extracted with ethyl acetate. ThepH value of the aqueous solution was adjusted to 8 with sodiumbicarbonate. The resulting solution was extracted with ethyl acetate.The combined extracts were dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in the title compound (120 mg,73%) as a solid.

Step 5: Preparation of tert-butyl(2S,4R)-4-fluoro-2-[([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate

A solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid(108 mg, 0.463 mmol, 1.097 equiv), DIEA (164 mg, 1.269 mmol, 3.0 equiv),HATU (193 mg, 0.508 mmol, 1.202 equiv), and[5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine(120 mg, 0.422 mmol, 1.000 equiv) in N,N-dimethylformamide (8 mL) wasstirred for 30 min at 25° C. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined extracts were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by a silica gel column eluting withethyl acetate/petroleum ether (1/5). This resulted in the title compound(180 mg, 85%) as light yellow oil.

Step 6: Preparation of(2S,4R)-4-fluoro-N-([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide

A solution of tert-butyl(2S,4R)-4-fluoro-2-[([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate(120 mg, 0.24 mmol, 1.00 equiv) and trifluoroacetic acid (4 mL) indichloromethane (20 mL) was stirred for 30 min at 25° C. The resultingmixture was concentrated under vacuum. The residue was dissolved inwater. The pH value of the solution was adjusted to 7-9 with aqueoussodium bicarbonate. The resulting solution was extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. This resultedin the title compound (140 mg, crude) as a light yellow solid.

Step 7: Preparation of(2S,4R)-4-fluoro-1-(4-fluorophenylsulfonyl)-N-((5-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide

A solution of(2S,4R)-4-fluoro-N-([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)pyrrolidine-2-carboxamide(225 mg, 0.563 mmol, 1.00 equiv), TEA (171 mg, 1.690 mmol, 3.0 equiv),and 4-fluorobenzene-1-sulfonyl chloride (132 mg, 0.678 mmol, 1.20 equiv)in dichloromethane (25 mL) was stirred for 12 h at 25° C. The mixturewas diluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The crude product was purified byPrep-HPLC to afford the title compound (20.7 mg) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 9.55 (s, 1H), 8.41 (s, 1H), 8.07 (s, 1H),7.88-7.91 (m, 2H), 7.44-7.52 (s, 1H), 7.23-7.26 (m, 2H), 4.99-5.12 (d,J=51.2 Hz, 1H), 4.83-4.90 (m, 1H), 4.29-4.39 (m, 2H), 4.07 (s, 3H),3.84-3.93 (m, 1H), 3.61-3.73 (m, 1H), 2.55-2.61 (m, 1H), 2.13-2.26 (m,1H).

Example 197 Preparation of(2S)-N-([3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxamide.

A mixture of (2S)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxylicacid (62 mg, 0.24 mmol, 1.20 equiv), HATU (114 mg, 0.30 mmol, 1.50equiv), DIEA (77 g, 595.78 mmol, 3.00 equiv), and[3-chloro-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]methanamine (55mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) was stirredfor 1 h at room temperature. The resulting solution was diluted withwater, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct (100 mg) was purified by Prep-HPLC to afford the title compound(63.3 mg, 61%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.55-8.52 (t, J=5.4 Hz, 1H),8.00-7.88 (m, 6H), 7.55-7.51 (t, J=8.8 Hz, 2H), 4.31-4.21 (m, 2H),3.73-3.71 (m, 1H), 3.58-3.55 (m, 1H), 2.21-2.14 (m, 2H).

Example 198 Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamide.Step 1: Preparation of tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid(0.1 g, 0.51 mmol),(6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methanamine (0.13 mg,0.51 mmol), iPr₂NEt (0.17 mL, 0.98 mmol), PyAOP (0.29 mg, 0.54 mmol) and4-DMAP (0.006 mg, 0.05 mmol) in DMF (3 mL) was stirred at roomtemperature for 3 h. The mixture was washed with saturated aqueousNaHCO₃ solution and brine, and extracted with EtOAc (2×). The combinedorganic layers were dried (Na₂SO₄) filtered, passed through a silica gelplug washing with EtOAc, and concentrated to provide crude tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate,which was used in the next step without any further purification.

Step 2: Preparation of2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride

To a solution of crude tert-butyl2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidine-1-carboxylate(0.22 g, 0.49 mmol), in CH₂Cl₂ (2 mL) was added 4 N HCl in dioxane (1mL, 4 mmol) and the mixture stirred at room temperature for 3 h. Themixture was concentrated under reduced pressure to provide2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride as a crude salt, which was used in the next step without anyfurther purification.

Step 3: Preparation of(S)-1-(4-fluorophenylsulfonyl)-2-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamide

A mixture of crude2-methyl-2-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methylcarbamoyl)azetidiniumchloride (0.085 g, 0.22 mmol), 4-fluorobenzene-1-sulfonyl chloride(0.047 mg, 0.24 mmol), and Et₃N (0.15 mL, 1.1 mmol) in CH₂Cl₂ (2 mL) wasstirred at room temperature for 12 h. The mixture was diluted with waterand extracted with CH₂Cl₂ (2×). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated. The resulting residue was purifiedby chiral SFC affording the title compound (22 mg) as the slower elutingisomer: ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J=1.9 Hz, 1H), 9.32 (d,J=1.2 Hz, 1H), 8.79 (dd, J=8.2, 1.7 Hz, 1H), 8.74 (t, J=5.9 Hz, 1H),8.18 (d, J=0.9 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 8.03-7.95 (m, 2H),7.54-7.43 (m, 2H), 4.66 (dd, J=17.4Hz, J=6.4 Hz, 1H), 4.49 (dd, J=17.4,J=5.4 Hz, 1H), 3.97-3.86 (m, 1H), 3.82-3.74 (m, 1H), 2.10-1.98 (m, 1H),1.54 (s, 3H).

Example 199 Preparation of(2S)-N-([3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxamide.

Step 1: Preparation of(2S)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxylic acid

4-Fluorobenzene-1-sulfonyl chloride (2.14 g, 11.00 mmol, 1.00 equiv) wasadded into a solution of (2S)-azetidine-2-carboxylic acid (1 g, 9.89mmol, 1.10 equiv) in saturated aqueous sodium hydroxide (6mL)/tetrahydrofuran (6 mL) at 0° C. The resulting mixture was stirredfor 18 h at room temperature. The mixture was extracted with ether. ThepH value of the aqueous solution was adjusted to 3 with 2 M hydrogenchloride. The resulting mixture was extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (1.7 g, 60%) as a whitesolid.

Step 2: Preparation of(2S)-N-([3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methyl)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxamide

A mixture of (2S)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxylicacid (62 mg, 0.24 mmol, 1.20 equiv), HATU (114 mg, 0.30 mmol, 1.50equiv), DIEA (77 mg, 0.60 mmol, 3.00 equiv), and[3-chloro-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl]methanamine(55 mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) wasstirred for 1 h at room temperature. The resulting solution was dilutedwith water, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The crudeproduct (100 mg) was purified by Prep-HPLC to afford the title compound(40.2 mg, 39%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.67 (s, 1H), 8.56-8.53 (m,1H), 8.44-8.41 (m, 1H), 8.09-8.07 (d, J=8.4 Hz, 1H), 7.98-7.93 (m, 2H),7.55-7.49 (m, 2H), 4.31-4.22 (m, 3H), 3.73-3.70 (m, 1H), 3.61-3.52 (m,1H), 2.27-2.11 (m, 2H).

Example 200 Preparation of(2S,4R)-1-[(4-fluorobenzene)sulfonyl]-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)azetidine-2-carboxamide.

Step 1: Preparation of methyl1-[(4-fluorobenzene)sulfonyl]-4-methylazetidine-2-carboxylate

4-Fluorobenzene-1-sulfonyl chloride (312 mg, 1.60 mmol, 1.20 equiv) wasadded into a solution of methyl 4-methylazetidine-2-carboxylate (400 mg,3.10 mmol, 1.00 equiv), 4-dimethylaminopyridine (240 mg, 1.96 mmol, 0.70equiv), and TEA (0.8 mL, 5.76 mmol, 4.00 equiv) in dichloromethane (12mL) at room temperature. The reaction was stirred for 12 h at roomtemperature. The mixture was diluted with water, extracted withdichloromethane, washed with brine, dried over anhydrous sodium sulfate,and concentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:5) to afford thetitle compound (220 mg, 25%) as orange oil.

Step 2: Preparation of1-[(4-fluorobenzene)sulfonyl]-4-methylazetidine-2-carboxylic acid

A mixture of methyl1-[(4-fluorobenzene)sulfonyl]-4-methylazetidine-2-carboxylate (180 mg,0.63 mmol, 1.00 equiv) and LiOH (15 mg, 0.63 mmol, 1.00 equiv) inmethanol (15 mL)/H₂O (1.5 mL) was stirred for 12 h at room temperature.The mixture was concentrated under vacuum. The residue was dissolved inwater. The pH value of the solution was adjusted to 3 with 1 M hydrogenchloride. The resulting mixture was extracted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, and concentrated undervacuum. This resulted in the title compound (0.12 g, 70%) as a whitesolid.

Step 3: Preparation of(2S,4R)-1-[(4-fluorobenzene)sulfonyl]-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)azetidine-2-carboxamide

A solution of1-[(4-fluorobenzene)sulfonyl]-4-methylazetidine-2-carboxylic acid (123mg, 0.45 mmol, 1.00 equiv),[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanaminehydrochloride (198 mg, 0.68 mmol, 1.50 equiv), DIEA (290 mg, 2.24 mmol,5.00 equiv), and HATU (259 mg, 0.68 mmol, 1.50 equiv) inN,N-dimethylformamide (4 mL) was stirred overnight at room temperature.The reaction was diluted with water, extracted with ethyl acetate,washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by a silica gel column elutingwith ethyl acetate/petroleum ether (30:100). The crude product waspurified by Chiral-Prep-HPLC to afford the title compound (96.9 mg, 42%)as a white solid. t_(R)=5.32 min (Lux Cellulose-4, 0.46×5 cm, 3 μm,Hex:EtOH=80:20, 1.0 ml/min).

¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (m, 1H), 9.31-9.30 (m, 1H), 9.08-9.04(m, 1H), 8.79-8.76 (m, 1H), 8.18 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.86(m, 2H), 7.43-7.38 (m, 2H), 4.77-4.72 (m, 1H), 4.51-4.45 (m, 3H),2.37-2.31 (m, 1H), 2.11-2.06 (m, 1H), 1.28-1.26 (m, 3H).

And(2R,4S)-1-[(4-fluorobenzene)sulfonyl]-4-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)azetidine-2-carboxamide(94.4 mg, 41%) was also isolated as a white solid. t_(R)=6.48 min (LuxCellulose-4, 0.46×5 cm, 3 μm, Hex:EtOH=80:20, 1.0 ml/min).

¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (m, 1H), 9.31-9.30 (m, 1H), 9.08-9.04(m, 1H), 8.79-8.76 (m, 1H), 8.18 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.87(m, 2H), 7.44-7.38 (m, 2H), 4.77-4.72 (m, 1H), 4.57-4.43 (m, 3H),2.39-2.31 (m, 1H), 2.11-2.03 (m, 1H), 1.28-1.26 (m, 3H).

Example 201 Preparationof(S)-1-(4-fluorophenylsulfonyl)-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)azetidine-2-carboxamide.

Preparation of the title compound follows the same general procedure asExample 198.

LCMS: m/z =496 (ret time: 4.78)

¹H NMR (400 MHz, DMSO) δ 9.49 (d, J=1.9 Hz, 1H), 9.30 (d, J=1.2 Hz, 1H),8.96 (t, J=5.5 Hz, 1H), 8.80 (dd, J=8.3, 1.9 Hz, 1H), 8.16 (d, J=0.9 Hz,1H), 8.09 (d, J=8.3 Hz, 1H), 8.05-7.98 (m, 2H), 7.56 (t, J=8.8 Hz, 2H),4.56 (ddd, J=40.0, 17.3, 6.0 Hz, 2H), 4.42-4.35 (m, 1H), 3.81-3.73 (m,1H), 3.59 (dd, J=16.9, 8.5 Hz, 1H), 2.34-2.15 (m, 2H), LCMS (ESI) m/z:496 [M+H]+

TABLE 4 MS Data for Exemplified Compounds. LC/MS (ESI+): Example m/z(M + H) 38 552.1 39 524.1 40 560.1 41 524.1 42 529.11 43 542.13 44 574.145 559.12 46 557.13 47 559.12 48 542.13 49 545.1 50 540.1 51 554.1 52559.12 53 528.11 54 545.11 55 509.13 56 545.11 57 542.12 58 547.1 59527.12 60 543.09 61 674.2 62 562.2 63 509.2 64 525.2 65 563.1 66 567.167 528.11 68 545.11 69 545.1 70 551.1 71 552.1 72 527.12 73 528.11 74550.16 75 526.12 76 542.1 77 542.1 78 551.1 79 552.1 80 536.14 81 527.1282 528.11 83 672.13 84 561.07 85 560.11 86 533.11 87 533.11 88 526.1 89545.2 90 527.2 91 545.2 92 539.1 93 545.1 94 526.12 95 544.11 96 541.197 545.1 98 545.1 99 551.1 100 551.1 101 561.1 102 546.1 103 546.1 104561.1 105 556.1 106 542.1 107 542.1 108 557.1 109 571.1 110 552.1 111543.1 112 551.1 113 545.1 114 545.1 115 545.1 116 556.1 117 563.1 118557.1 119 545.1 120 545.1 121 577.1 122 545.1 123 522.1 124 572.1 125560.1 126 559.1 127 558.1 128 519.1 129 509.1 130 601.1 131 527.1 132547.1 133 541.2 134 545.1 135 545.1 136 528.1 137 549.1 138 541.1 139544.1 140 545.1 141 545.1 142 542.1 143 527.2 144 551.1 145 543.1 146550.1 147 559.1 148 531.1 149 533.2 150 545.1 151 556.1 152 542.1 153546.1 154 528.2 155 499.2 156 546.1 157 528.2 158 561.2 159 542.2 160524.2 161 544.2 162 543.2 163 545.2 164 552.2 165 558.2 166 552.1 167546.1 168 527.2 169 542.1 170 601.1 171 546.2 172 522.2 173 550.2 174550.2 175 550.2 176 546.2 177 543.2 178 542.2 179 556.2 180 546.2 181539.2 182 539.2 183 539.2 184 562.1 185 572.1 186 524.1 187 559.2 188558.2 189 553.1 190 618.1 191 542.1 192 562.1 193 542.1 194 538.5 195528.5 196 558.1 197 517.1 198 510.2 199 518.1 200 510. 201 496

IC50 Determinations of Exemplified Compounds.

IC50s (effective concentration) of compounds on the human and rat TRPA1channels were determined using a FLIPR Tetra instrument. CHO cellsexpressing TRPA1 were plated into 384-well plates, incubated overnightat 37C., and loaded with BD calcium indicator dye for 1 hr at 37° C.followed by 15 minutes. at room temperature. The assay buffer was Hank'sBalanced Salt Solution (HBSS) containing 20 mM HEPES (pH readjusted to7.4) along with 0.02% BSA.

Following dye load and plate cool down, compounds were added to thecells using FLIPR Tetra. Plates were then incubated with compounds for20 minutes at room temperature prior to adding agonist. Following thisincubation, ˜EC80 concentration of cinnamaldehyde (75 uM for human TRPA1and 45 uM for rat TRPA1) was added to active the channels and block ofcinnamaldehyde induced calcium influx was measured.

IC50s were fit with a standard Hill function, keeping the Hillcoefficient (n) fixed to 1.5. Fixing the Hill coefficient will generallyreduce variability of the IC50 determination. The IC50s wereindividually examined to make sure the MIN and MAX points were setcorrectly prior to validation of the results. Data for representativecompounds of formula I and II is provided in Table 5 below.

TABLE 5 IC50 Determinations of Exemplified Compounds. hTRPA1 AUC ExampleIC₅₀ Number Structure (μM)  38

0.014  39

0.045  40

0.291  41

0.005  42

0.251  43

0.047  44

0.048  45

0.024  46

0.020  47

0.011  48

0.152  49

0.009  50

0.060  51

0.052  52

0.016  53

0.411  54

0.013  55

0.033  56

0.011  57

0.005  58

0.014  59

0.029  60

0.055  61

0.071  62

0.014  63

0.318  64

0.041  65

0.040  66

0.022  67

0.290  68

0.007  69

0.014  70

0.023  71

0.176  72

0.007  73

0.129  74

0.192  75

0.031  76

0.039  77

0.053  78

0.007  79

0.009  80

0.044  81

0.187  82

0.189  83

0.0546  84

0.014  85

0.771  86

0.119  87

0.103  88

0.041  89

0.020  90

0.062  91

0.014  92

0.087  93

0.014  94

0.029  95

0.012  96

0.162  97

0.024  98

0.004  99

0.428 100

0.449 101

0.033 102

0.066 103

0.026 104

0.072 105

0.128 106

0.28 107

0.090 108

0.256 109

0.164 110

0.165 111

0.007 112

0.048 113

0.161 114

0.026 115

0.013 116

0.047 117

0.224 118

0.037 119

0.052 120

0.049 121

0.741 122

0.014 123

0.156 124

0.113 125

0.009 126

0.025 127

0.097 128

0.404 129

0.099 130

0.052 131

0.102 132

0.126 133

0.059 134

0.023 135

0.011 136

0.021 137

0.078 138

0.025 139

0.016 140

0.020 141

0.068 142

0.092 143

0.015 144

0.056 145

0.021 146

0.078 147

0.049 148

0.046 149

0.034 150

0.046 151

0.161 152

0.163 153

0.068 154

0.097 155

0.134 156

0.109 157

0.103 158

0.004 159

0.018 160

0.086 161

0.009 162

0.011 163

0.043 164

0.032 165

0.066 166

0.013 167

0.038 168

0.075 169

0.116 170

0.089 171

0.211 172

0.038 173

0.111 174

0.012 175

0.086 176

0.008 177

0.005 178

0.175 179

0.062 180

0.026 181

0.010 182

0.021 183

0.003 184

0.010 185

0.155 186

0.004 187

0.006 188

0.008 189

0.055 190

0.052 191

0.027 192

0.042 193

0.015 194

0.381 195

0.795 196

0.134 197

0.015 198

0.059 199

0.138 200

0.333 201

0.268

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims. All documents cited to or relied uponherein are expressly incorporated by reference.

We claim:
 1. A compound of formula II:

wherein: (1) A is

B is B¹ and R⁵ is R^(5a); or (2) A is

B is B² and R⁵ is R^(5b); or (3) A is

B is B³ and R⁵ is R^(5a); or (4) A is

B is B⁴ and R⁵ is R^(5a); or (5) A is

B is B¹ and R⁵ is R^(5a); or (6) A is

B is B⁵ and R⁵ is R^(5a); or (7) A is

B is B³ and R⁵ is R^(5a); B is a 5-membered heteroaryl comprising 2 or 3nitrogen atoms in the ring that is optionally substituted with one ormore groups independently selected from halogen, (C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —CN, and NR⁶ ₂ (C₃-C₇)cycloalkyl; R¹ is a phenyl or5-membered heteroaryl, wherein R¹ is optionally substituted with one ormore groups independently selected from halogen, —CN, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl; R² is halogen, (C₁-C₆)alkyl or CN, wherein any(C₁-C₆)alkyl of R² is optionally substituted with one or more groupsindependently selected from halogen, —OH and —O(C₁-C₆)alkyl; each R^(3a)is independently selected from H, halogen and (C₁-C₆)alkyl; one R^(3b)group is halogen, —CN, or (C₁-C₆)alkyl and the remaining R^(3b) groupsare independently selected from H, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;one R^(3b)′ group is halogen, (C₁-C₆)alkyl, —CN, or (C₁-C₆)haloalkyl andthe remaining R^(3b)′ groups are independently selected from H,(C₁-C₆)alkyl and (C₁-C₆)haloalkyl; two R^(3c) groups attached todifferent non-adjacent carbon atoms or adjacent carbon atoms arecombined to form a (C₁-C₄)alkyl linker or a (C₁-C₂)alkyl-O-(C₁-C₂)alkyllinker, wherein the (C₁-C₄)alkyl linker or (C₁-C₂)alkyl-O-(C₁-C₂)alkyllinker is optionally substituted with one or more groups independentlyselected from halogen and (C₁-C₆)alkyl, and the remaining R^(3c) groupsare independently selected from H, halogen and (C₁-C₆)alkyl; each R^(3d)group is independently selected from H, halogen, (C₁-C₆)alkyl, and —CN,wherein any (C₁-C₆)alkyl of R^(3d) is optionally substituted with one ormore groups independently selected from halogen, —OH and —O(C₁-C₆)alkyl;one R^(3e) group is halogen, —CN or (C₁-C₆)alkyl and the remainingR^(3e) groups are independently selected from H, (C₁-C₆)alkyl and(C₁-C₆)haloalkyl; two R^(3f) groups attached to the same carbon atom arecombined to form a (C₂-C₄)alkyl linker, wherein the (C₂-C₄)alkyl linkeris optionally substituted with one or more groups independently selectedfrom halogen and (C₁-C₆)alkyl, and the remaining R^(3f) groups areindependently selected from H, halogen and (C₁-C₆)alkyl; R⁴ is H,(C₁-C₆)alkyl or (C₁-C₆)haloalkyl; R⁵ is R^(5a) or R⁵¹); R⁵a is a phenyl,5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-memberedheterocycle or (C₃-C₈)cycloalkyl, wherein any phenyl, 5-memberedheteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or(C₃-C₈)cycloalkyl of R^(5a) is optionally substituted with one or moregroups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —S(C₁-C₆)alkyl,—S(C₁-C₆)haloalkyl, oxo and —O—(C₁-C2)alkyl-O- optionally substitutedwith one or more halogen, which —O—(C₁-C₂)alkyl-O- group is bonded totwo adjacent carbon atoms of any phenyl, 5-membered heteroaryl,6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or(C₃-C₈)cycloalkyl of R^(5a); R^(5b) is a phenyl, 5-membered heteroaryl,6-membered heteroaryl or 4, 5, 6, 7 or 8-membered heterocycle, whereinany phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7 or8-membered heterocycle of R^(5b) is optionally substituted with one ormore groups independently selected from halogen, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CN, (C₃-C₇)cycloalkyl optionally substituted with oneor more halogen, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —OH,—S(C₁-C₆)alkyl, —S(C₁-C₆)haloalkyl, and NR⁶ ₂, and wherein any5-membered heterocycle of R^(5b) is substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,—CN, (C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl,—S(C₁-C₆)alkyl and —S(C₁-C₆)haloalkyl; and each R⁶ is independently H or(C₁-C₆)alkyl; or pharmaceutically acceptable a salt thereof.
 2. Thecompound of claim 1, wherein: (1) A is

B is B¹ and R⁵ is R^(5a); or (2) A is

B is B² and R⁵ is R^(5b); or (3) A is

B is B³ and R⁵ is R^(5a); or (4) A is

B is B⁴ and R⁵ is R^(5a); or (5) A is

B is B¹ and R⁵ is R^(5a); or (6) A is

B is B⁵ and R⁵ is R^(5a); or (7) A is

B is B³ and R⁵ is R.
 3. The compound of claim 1 wherein each R^(3a) isindependently H or F.
 4. The compound of claim 1 wherein one R^(3a) is Fand the remaining R^(3a) groups are H.
 5. The compound of claim 1wherein each R^(3a) is H.
 6. The compound of claim 1, wherein R² is(C₁-C₆)alkyl or CN, wherein any (C₁-C₆)alkyl of R² is optionallysubstituted with one or more groups independently selected from halogen,—OH and —O(C₁-C₆)alkyl.
 7. The compound of claim 1, wherein R² is —CH₃,—CH₂OH, —CHF₂, —CH₂OCH₃ or CN.
 8. The compound of claim 1,wherein R² is—CH₃.
 9. The compound of claim 1,wherein B is a pyrazolyl or triazolyl,each of which is optionally substituted with one or more groupsindependently selected from halogen, (C₁-C₆)alkyl, —O(C₁-C₆)alkyl and(C₃-C₇)cycloalkyl.
 10. The compound of claim 1, wherein B is:

wherein each R^(Z1) is independently selected from H, halogen,(C₁-C₆)alkyl, —O(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl.
 11. The compound ofclaim 1, wherein one R^(3b) group is F and the remaining R^(3b) groupsare H, and one R^(3b)′ group is F and the remaining R^(3b)′ groups areH.
 12. The compound of claim 1, wherein (1) the A group

is:

(2) the A group

is:

and (3) the A group

is:


13. A pharmaceutical composition, comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.
 14. A method for treating arespiratory disorder in a mammal comprising, administering a compound ofclaim 1 or a pharmaceutically acceptable salt thereof to the mammal.